CN115019932A - System and method for predicting dosage of exogenous follicle-stimulating hormone drug given in COS period - Google Patents

System and method for predicting dosage of exogenous follicle-stimulating hormone drug given in COS period Download PDF

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CN115019932A
CN115019932A CN202210886125.3A CN202210886125A CN115019932A CN 115019932 A CN115019932 A CN 115019932A CN 202210886125 A CN202210886125 A CN 202210886125A CN 115019932 A CN115019932 A CN 115019932A
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徐慧玉
李蓉
乔杰
冯国双
韩勇
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Peking University Third Hospital Peking University Third Clinical Medical College
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Abstract

Disclosed is a system for predicting the dose of exogenous FSH to be administered to a subject in a COS cycle, comprising: a data acquisition module for acquiring age, basal AMH, basal FSH or Δ INHB, basal AFC data of the subject; an exogenous FSH drug dose calculation module for: calculating the predicted NROs of the subject by performing a first calculation on the obtained data; performing a second calculation of the data obtained to calculate a ratio of predicted NROs for the subject to the dose of exogenous FSH drug administered to the subject; calculating the exogenous administration based on the first calculated predicted NROs and the ratioFSH drug dose. A corresponding prediction method is also disclosed. According to the application, the dosage of the exogenous FSH drug is obtained by firstly calculating and predicting the NROs and then calculating the predicted ovarian sensitivity, namely the ratio of the predicted NROs to the dosage of the exogenous FSH drug, and under the condition that only one unknown variable of the dosage of the exogenous FSH drug exists in the variables of the result of predicting the ovarian sensitivity, the dosage of the exogenous FSH drug can be predicted, and the model R 2 >0.9。

Description

System and method for predicting dosage of exogenous follicle-stimulating hormone drug given in COS period
Technical Field
The application relates to the technical field of medical treatment, in particular to a system and a method for obtaining initial dose and adjusted dose of exogenous Follicle Stimulating Hormone (FSH) medicine given to a subject by calculating and predicting ovarian sensitivity in a controlled ovarian stimulation period, namely predicting the ratio of the number of obtained ova to the dose of the exogenous FSH medicine.
Background
For women undergoing Controlled Ovarian Stimulation (COS) and in vitro fertilization/Intracytoplasmic sperm injection (IVF/ICSI) cycles, The number of eggs obtained, i.e., The number of oocytes obtained after COS treatment (NROs), is considered to be a strong surrogate prognostic marker for successful pregnancy. Optimal NROs help to improve Live-birth-rate (LBR).
Infertility is defined as the failure to become pregnant after a regular and unprotected sexual intercourse for 12 months. The infertility rate of women of childbearing age in China is up to 12-15%. Assisted Reproductive Technology (ART) is the most common and most effective means for treating infertility. Meanwhile, Controlled Ovarian Stimulation (COS), In Vitro Fertilization (IVF) and Embryo Transfer (ET) are the most common and most effective types of ART. Personalized COS is a milestone in ART history. The selection of an appropriate dose of exogenous Follicle Stimulating Hormone (FSH) is crucial for COS. There are two important points in time for individualized COS, one when the initial dose is selected at the beginning of each new treatment cycle, and one when the dose is adjusted within a given COS cycle.
The selection of the initial dosage of ovulation-promoting treatment is very important, and doctors in clinic often estimate the expected egg number by combining the size and the number of follicles under ultrasound in the treatment process with the growth change of LH (luteinizing hormone), estradiol (E2) and progesterone (P) according to personal experience and adjust the dosage of the ovulation-promoting medicament, but at present, the adjustment of exogenous FSH medicament dosage in the ovulation-promoting process in the international range mainly depends on subjective experience and has no uniform standard. The research team develops a system and a method for predicting ovarian responsiveness for ovulation induction treatment by using a basic ovarian reserve index (index before ovulation induction treatment), a result variable of the system is low ovarian response probability, people with similar low response probability are classified according to people, and a dosage suggestion is given, although the dosage suggestion has certain advancement, no dosage exists in the result variable, the essence is the combination of the low response probability prediction and clinical experience, although the method is a common practice in the world, the method is obviously an empirically judged component, is not intelligent enough, and is worthy of further improvement.
In addition, some researchers have used models to predict the number of eggs obtained (NROs) and then combined the predicted NROs with clinical assumptions to recommend a certain initial dose of exogenous FSH in patients with similar ovarian responses. The main outcome variable of these models is NROs. La Marca et al propose a new idea to predict the initial dose of exogenous FSH drugs using the ratio of actual NROs to actual initial dose as the outcome variable. They first included the dose variable in the outcome variable, i.e., the dose was included in the model rather than being empirically determined. They used three basic indicators of age, FSH and anti-Mullerian hormone (AMH) to predict ovarian sensitivity, i.e., actual NROs divided by actual initial dose of exogenous FSH, model R 2 Is 0.3. However, the outcome variable, i.e. the ratio of the actual NROs to the initial dose of exogenous FSH, both of which are unknown prior to ovarian stimulation, must be assumed prior to the final calculated dose. They assumed that all human NROs were 9, and then the initial dose of exogenous FSH was calculated. Although this study has great innovative value for predicting the initial dose of exogenous FSH compared to previous models, the fixation of NROs at 9 lacks individualized guidance and is not in line with the actual situation in most patients.
Disclosure of Invention
Selection of an appropriate dose of exogenous Follicle Stimulating Hormone (FSH) is critical for the controlled ovarian stimulation Cycle (COS). The standard fixed dose of exogenous FSH is not suitable for all women because of their ovarian reserve and ovarian responseThere are differences, and the determination of the most appropriate initial and adjusted doses of exogenous FSH drugs based on individualized ovarian reserve and the drug response of the ovaries to exogenous FSH has been the goal of many physicians. To date, no simple, adaptable online tool has been developed. Accordingly, the present application provides a system and method for predicting the initial and adjusted doses of an exogenous FSH drug to be administered to a subject during a controlled ovarian stimulation cycle based on personalized ovarian reserve and response to the exogenous FSH drug, which can be predicted based on basic criteria, a prediction model R of the present application 2 Greater than 0.9, much higher than prior art models.
In summary, the present application relates to the following:
1. a system for predicting a dose of an exogenous Follicle Stimulating Hormone (FSH) drug administered to a subject in a controlled ovarian stimulation cycle, comprising:
a data acquisition module for acquiring data of age, basal anti-mullerian hormone (AMH) level, basal Follicle Stimulating Hormone (FSH) level or inhibin B level dynamic change (Δ INHB), basal Antral Follicle Count (AFC) of a subject; and
an exogenous Follicle Stimulating Hormone (FSH) drug dose calculation module to: calculating the data acquired by the data acquisition module for the first time so as to calculate the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation induction period; performing a second calculation on the data acquired by the data acquisition module, thereby calculating the ratio of the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation induction cycle to the dosage of the exogenous FSH medicament, namely predicting the ovarian sensitivity; calculating the dose of exogenous FSH drug to be administered to the subject based on the first calculated predicted egg counts (predicted NROs) and the second calculated ratio.
2. The system of item 1, wherein,
the subject is to be treated by standard ovulation induction, and the number of eggs obtained (NROs) of the subject is the number of mature oocytes with the diameter of more than 10mm, preferably more than 15mm, obtained after hCG injection induced follicular maturation after 1-2 dominant follicles in the ovarian stimulation process of the subject after ovulation induction treatment reach more than 18 mm.
3. The system of item 1 or 2, wherein,
in the data acquisition module, the obtained basal anti-mullerian hormone (AMH) level refers to the anti-mullerian hormone concentration in venous blood of the subject at any time point during the menstruation period prior to ovulation induction treatment.
4. The system according to any one of items 1 to 3, wherein,
in the data collection module, the obtained basal Follicle Stimulating Hormone (FSH) level refers to the follicle stimulating hormone concentration in venous blood of a female subject at day 2-4 of menstruation before ovulation induction treatment.
5. The system according to any one of items 1 to 4, wherein,
in the data acquisition module, the obtained basal Antral Follicle Count (AFC) is the number of all visible follicles with a diameter of 2-10mm in two ovaries of a female subject on day 2 of menstruation, counted by vaginal ultrasound.
6. The system according to any one of items 1 to 5, wherein,
in the data collection module, the obtained dynamic change in inhibin B levels (Δ INHB) refers to the dynamic change in inhibin B levels (Δ INHB) in the early phase of ovulation induction therapy, preferably the difference between the concentration of serotonin B at day 6 of menstruation and the concentration of inhibin B in venous blood at day 2 of menstruation in a female subject undergoing a GnRH antagonist regimen for the ovulation induction therapy cycle.
7. The system according to any one of items 1 to 6, wherein,
the data acquisition module is for acquiring data of age, basal anti-mullerian hormone (AMH) level, basal Follicle Stimulating Hormone (FSH) level, basal Antral Follicle Count (AFC) of the subject;
the exogenous Follicle Stimulating Hormone (FSH) drug dose calculation module is configured to: calculating the data acquired by the data acquisition module for the first time so as to calculate the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation induction period; performing a second calculation on the data acquired by the data acquisition module, thereby calculating the ratio of the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation induction cycle to the initial dose of the exogenous FSH medicament, namely predicting the ovarian sensitivity; an initial dose of exogenous FSH drug to be administered to the subject is calculated based on the first calculated predicted egg counts (predicted NROs) and the second calculated ratio.
8. The system of item 7, wherein,
in the exogenous FSH drug dose calculation module, a formula one for calculating the predicted number of eggs (predicted NROs) obtained from the subject, which is obtained by fitting data on the age, the basal anti-mullerian hormone (AMH) level, the basal Follicle Stimulating Hormone (FSH) level, the basal sinus follicle count (AFC), and the actual number of eggs obtained from the patient who has received standard GnRH antagonist based ovulation induction therapy in the existing database, is stored in advance.
9. The system of item 8, wherein,
in the exogenous FSH drug dose calculation module, the formula is a first calculation formula obtained by fitting the data of the age, the basic anti-Mullerian hormone (AMH) level, the basic Follicle Stimulating Hormone (FSH) level, the basic Antral Follicle Count (AFC) and the actual egg acquisition number (fate variable) of a patient who is subjected to ovulation induction treatment by a standard GnRH antagonist scheme in an existing database by using a fate variable negative binomial distribution;
the formula can calculate predicted harvested egg numbers (predicted NROs) of the subject using age data of the subject, basal anti-mullerian hormone (AMH) level data of the subject, basal Follicle Stimulating Hormone (FSH) level data of the subject, and basal sinus follicle count (AFC) data of the subject acquired by the data acquisition module.
10. The system of item 9, wherein the first formula is:
predicting NROs ═ EXP (a + b age + c basal FSH + d LN [ basal AMH ] + f LN [ basal AFC ]);
wherein a is any value selected from 1.5576128-2.6037078, preferably 2.0806603;
b is any value of-0.019097-0.0044064, preferably-0.007345;
c is selected from any value of-0.045234 to-0.004054, preferably-0.024644;
d is any value of 0.348168-0.4948875, preferably 0.4215277;
f is any value of 0.0415663-0.2566199, preferably 0.1490931.
11. The system of item 10, wherein,
a second formula for calculating the predicted ovarian sensitivity of the subject, namely the ratio of the predicted number of ova obtained (predicted NROs) to the initial dose of the exogenous FSH drug, which is obtained by fitting data of the ratio of the predicted number of ova obtained (predicted NROs) calculated by the first formula to the average daily dose of the exogenous FSH drug used by the patient based on the age, the level of basal anti-mullerian hormone (AMH), the level of basal Follicle Stimulating Hormone (FSH), the basal sinus follicle count (AFC) of the patient who has undergone ovulation induction treatment by the standard GnRH antagonist scheme in the existing database, is stored in advance in the exogenous FSH drug dose calculation module;
wherein the average daily dose of the exogenous FSH drug administered to the patient is the ratio of the total dose of the exogenous FSH drug administered to the patient during the past ovulation induction treatment with the standard GnRH antagonist regimen to the number of days the exogenous FSH drug was administered.
12. The system of item 11, wherein,
in the exogenous FSH drug dose calculation module, the second formula is capable of calculating the predicted ovarian sensitivity of the subject, i.e., the ratio of the predicted number of harvested ova (predicted NROs) to the initial dose of the exogenous FSH drug administered to the subject, using the age data of the subject, the basal anti-mullerian hormone (AMH) level data of the subject, the basal Follicle Stimulating Hormone (FSH) level data of the subject, and the basal sinus follicle count (AFC) data of the subject obtained by the data acquisition module.
13. The system of item 11 or 12, wherein the formula two is:
predicted ovarian sensitivity in subjects, i.e., the predicted initial dose of NROs/exogenous FSH drug calculated by equation one (EXP) (g + h age + i basal FSH + j LN [ basal AMH ] + k basal AFC)
Wherein g is selected from any value of-3.167587 to-2.751518, preferably-2.959552;
h is selected from any value of-0.025951 to-0.016355, preferably-0.021153;
i is selected from any value of-0.048143 to-0.025727, preferably-0.036935;
j is any value selected from 0.5174476-0.6075545, preferably 0.5625011;
k is any value of 0.0241595-0.0365579, preferably 0.0303587.
14. The system of item 13, wherein the initial dose of the exogenous FSH drug to be administered to the subject is calculated using equation three based on the first calculated predicted resulting egg count (predicted NROs) and the second calculated ratio, wherein equation three is:
initial dose of exogenous FSH drug was Round (predicted NROs calculated by equation one/predicted ovarian sensitivity calculated by equation two, 0).
15. The system according to any one of items 1 to 6, wherein,
the data acquisition module is used for acquiring data of age, basal anti-mullerian hormone (AMH) level, basal Antral Follicle Count (AFC) and inhibin B level dynamic change (delta INHB) of a subject;
the exogenous Follicle Stimulating Hormone (FSH) drug dose calculation module is to: calculating the data acquired by the data acquisition module for the first time so as to calculate the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation induction period; performing a second calculation on the data acquired by the data acquisition module, thereby calculating the ratio of the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation-promoting cycle to the adjusted dose of the exogenous FSH medicament, namely predicting the ovarian sensitivity; an adjusted dose of exogenous FSH drug to be administered to the subject is calculated based on the first calculated predicted egg counts (predicted NROs) and the second calculated ratio.
16. The system of item 15, wherein,
in the exogenous FSH drug dose calculation module, i.e., according to the ovulation induction treatment early dynamic change index and the basic index, the module comprises a fourth formula for calculating the predicted number of eggs obtained from the subject, which is obtained by fitting the age, the basal anti-mullerian hormone (AMH) level, the basal sinus follicle count (AFC), the inhibin B level dynamic change (Δ INHB) and the actual number of eggs obtained of the patient who has undergone ovulation induction treatment by the standard GnRH antagonist regimen in the existing database in advance.
17. The system of item 16, wherein,
in the exogenous FSH drug dose calculation module, the fourth formula is a calculation formula obtained by fitting the data of the age, the basic anti-mullerian hormone (AMH) level, the basic Antral Follicle Count (AFC), the inhibin B level dynamic change (delta INHB) and the actual egg acquisition number (fate variable) of the patient who is subjected to ovulation induction treatment by the standard GnRH antagonist scheme in the existing database by utilizing fate variable negative binomial distribution;
the fourth equation is capable of calculating predicted harvested eggs (predicted NROs) of the subject using the age data of the subject, the basal anti-mullerian hormone (AMH) level data of the subject, the basal sinus follicle count (AFC) data of the subject, and the inhibin B level dynamics (Δ INHB) data of the subject acquired by the data acquisition module.
18. The system of item 17, wherein the formula four is:
predicting NROs ═ EXP (w + m age + n LN [ basal AMH ] + o LN [ Δ INHB ] + p LN [ basal AFC ]);
wherein w is any value selected from-0.447201-0.9161863, preferably 0.2344927;
m is any value of-0.017165-0.0039328, preferably-0.006616;
n is any value of 0.1318094-0.3113979, preferably 0.2216036;
o is any value of 0.1901643-0.3850919, preferably 0.2876281;
p is any value of 0.0541966-0.2338079, preferably 0.1440023.
19. The system of item 18, wherein,
in the exogenous FSH medicament dose calculation module, a fifth formula for calculating the predicted ovarian sensitivity of the subject, namely the ratio of the predicted number of eggs obtained (predicted NROs) to the adjusted dose of the exogenous FSH medicament, is stored in advance, wherein the fifth formula is formed by fitting data of the ratio of the predicted number of eggs obtained (predicted NROs) calculated by the fourth formula to the average daily dose of the exogenous FSH medicament used by the patient, the data of the age, the level of basic anti-Mullerian hormone (AMH), the basic sinus follicle count (AFC), the dynamic change of inhibin B level (delta INHB) of the patient subjected to ovulation promotion treatment by the standard GnRH antagonist scheme in the existing database;
wherein the average daily dose of the exogenous FSH drug administered to the patient is the ratio of the total dose of the exogenous FSH drug administered to the patient during the past ovulation induction treatment with the standard GnRH antagonist regimen to the number of days the exogenous FSH drug was administered.
20. The system of item 19, wherein,
in the exogenous FSH drug dose calculation module, the formula five can calculate the predicted ovarian sensitivity of the subject, i.e., the ratio of the predicted number of harvested ova (predicted NROs) to the adjusted dose of the exogenous FSH drug administered to the subject, using the age data of the subject, the basal anti-mullerian hormone (AMH) level data of the subject, the basal sinus follicle count (AFC) data of the subject, and the dynamictic change in inhibin B level (Δ INHB) data of the subject, acquired by the data acquisition module.
21. The system of item 19 or 20, wherein the formula five is:
predicted ovarian sensitivity in subjects, i.e., the predicted NROs/exogenous FSH drug adjusted dose calculated by equation four (q + r age + s LN [ basal AMH ] + t basal AFC + u LN [ Δ INHB ])
Wherein q is any value selected from-5.63461 to-5.108612, preferably-5.371611;
r is selected from any value of-0.0264 to-0.015183, preferably-0.020792;
s is any value of 0.2696292-0.3684551, preferably 0.3190421;
t is any value of 0.0273504-0.0399372, preferably 0.0336438;
u is any value of 0.3327566-0.3940448, preferably 0.3634007.
22. The system of item 21, wherein the adjusted dose of exogenous FSH drug to be administered to the subject is calculated using equation six based on the first calculated predicted resulting egg counts (predicted NROs) and the second calculated ratio, wherein equation six is:
exogenous FSH drug adjusted dose-Round (predicted NROs calculated by equation four/predicted ovarian sensitivity calculated by equation five, 0).
23. A method for predicting the dosage of an exogenous FSH drug to be administered to a subject in a controlled ovarian stimulation cycle, comprising:
a data acquisition step: obtaining data on age, basal anti-mullerian hormone (AMH) level, basal Follicle Stimulating Hormone (FSH) level or dynamic change in inhibin B level (Δ INHB), basal Antral Follicle Count (AFC) of the subject; and
calculating the dose of the exogenous FSH medicament: calculating the predicted number of eggs (predicted NROs) obtained from the subject during the ovulation induction cycle by performing a first calculation on the data obtained in the data acquisition step; performing a second calculation on the acquired data in the data acquisition module, thereby calculating the ratio of the predicted number of eggs (predicted NROs) to the dose of the exogenous FSH medicament in the ovulation induction cycle of the subject, namely predicting the ovarian sensitivity; the dose of exogenous FSH drug to be administered to the subject is calculated based on the first calculated predicted egg counts (predicted NROs) and the second calculated ratio.
24. The method of item 23, wherein,
the subject is to be treated by standard ovulation induction, and the number of eggs obtained (NROs) of the subject is the number of mature oocytes with the diameter of more than 10mm, preferably more than 15mm, obtained after hCG injection induced follicular maturation after 1-2 dominant follicles in the ovarian stimulation process of the subject after ovulation induction treatment reach more than 18 mm.
25. The method of item 23 or 24, wherein,
in the data collection step, the obtained basal anti-mullerian hormone (AMH) level refers to the anti-mullerian hormone concentration in venous blood of the subject at any time point during the menstruation period prior to ovulation induction treatment.
26. The method of any one of items 23 to 25, wherein,
in the data collection step, the obtained basal Follicle Stimulating Hormone (FSH) level is the follicle stimulating hormone concentration in venous blood of a female subject at day 2 to 4 of menstruation before ovulation induction treatment.
27. The method of any one of items 23 to 26, wherein,
in the data collection step, the obtained basal Antral Follicle Count (AFC) is the number of all visible follicles with a diameter of 2-10mm in two ovaries of a female subject on day 2 of menstruation, counted by vaginal ultrasonography B.
28. The method of any one of items 23 to 27, wherein,
in the data collection step, the obtained dynamic change in inhibin B level (Δ INHB) refers to the dynamic change in inhibin B level (Δ INHB) in the early stages of ovulation induction treatment, and preferably is the difference between the concentration of inhibin B in the female subject on day 6 of menstruation and the concentration of inhibin B in venous blood on day 2 of menstruation when the female subject receives the ovulation induction treatment cycle of a GnRH antagonist regimen.
29. The method of any one of items 23 to 28, wherein,
acquiring data of age, basal anti-mullerian hormone (AMH) level, inhibin B level dynamics (Δ INHB), basal Antral Follicle Count (AFC) of the subject in a data acquisition step;
in the step of calculating the exogenous FSH medicament dose, the data acquired by the data acquisition module are calculated for the first time, so that the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation-promoting period is calculated; performing a second calculation on the data acquired by the data acquisition module, thereby calculating the ratio of the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation-promoting cycle to the adjusted dose of the exogenous FSH medicament, namely predicting the ovarian sensitivity; an adjusted dose of exogenous FSH drug to be administered to the subject is calculated based on the first calculated predicted egg counts (predicted NROs) and the second calculated ratio.
30. The method of item 29, wherein,
in the exogenous FSH drug dose calculation step, a formula one for calculating the predicted number of eggs obtained (predicted NROs) from the subject, which is obtained by fitting data on the age of a patient who has undergone ovulation induction treatment using a standard GnRH antagonist regimen, the basal anti-mullerian hormone (AMH) level, the dynamic change in inhibin B level (Δ INHB), the basal sinus follicle count (AFC), and the actual number of eggs obtained in an existing database, is stored in advance.
31. The method of item 30, wherein,
in the exogenous FSH drug dose calculation step, the formula is a first calculation formula obtained by fitting the data of the age, the basal anti-mullerian hormone (AMH) level, the basal Follicle Stimulating Hormone (FSH) level, the basal Antral Follicle Count (AFC) and the actual number of eggs obtained (outcome variable) of the patient who has received standard GnRH antagonist regimen for ovulation induction in the existing database to a negative binomial distribution of the outcome variable;
the equation can be used to calculate predicted harvested egg numbers (predicted NROs) for the subject using the age data for the subject, the basal anti-mullerian hormone (AMH) level data for the subject, the basal Follicle Stimulating Hormone (FSH) level data for the subject, and the basal sinus follicle count (AFC) data for the subject obtained from the data collection step.
32. The method of item 31, wherein the formula one is:
predicting NROs ═ EXP (a + b age + c basal FSH + d LN [ basal AMH ] + f LN [ basal AFC ]);
wherein a is any value selected from 1.5576128-2.6037078, preferably 2.0806603;
b is any value of-0.019097-0.0044064, preferably-0.007345;
c is selected from any value of-0.045234 to-0.004054, preferably-0.024644;
d is any value of 0.348168-0.4948875, preferably 0.4215277;
f is any value of 0.0415663-0.2566199, preferably 0.1490931.
33. The method of item 32, wherein,
in the exogenous FSH drug dose calculation step, a second formula for calculating the predicted ovarian sensitivity of the subject, i.e., the ratio of the predicted number of eggs obtained (predicted NROs) to the initial dose of the exogenous FSH drug, which is obtained by fitting data of the ratio of the predicted number of eggs obtained (predicted NROs) calculated by the first formula to the average daily dose of the exogenous FSH drug used by the patient, based on the age, the level of basal anti-mullerian hormone (AMH), the level of basal Follicle Stimulating Hormone (FSH), the basal sinus follicle count (AFC) of the patient who has undergone ovulation induction treatment by the standard GnRH antagonist regimen in the existing database, is stored in advance;
wherein the average daily dose of the exogenous FSH drug administered to the patient is the ratio of the total dose of the exogenous FSH drug administered to the patient during the past ovulation induction treatment with the standard GnRH antagonist regimen to the number of days the exogenous FSH drug was administered.
34. The method of item 33, wherein,
in the exogenous FSH drug dose calculation step, the second formula is capable of calculating the predicted ovarian sensitivity of the subject, i.e., the ratio of the predicted number of harvested ova (predicted NROs) to the initial dose of the exogenous FSH drug administered to the subject, using the age data of the subject, the basal anti-mullerian hormone (AMH) level data of the subject, the basal Follicle Stimulating Hormone (FSH) level data of the subject, and the basal sinus follicle count (AFC) data of the subject, acquired by the data acquisition module.
35. The method of item 33 or 34, wherein the formula two is:
predicted ovarian sensitivity in subjects, i.e., the predicted initial dose of NROs/exogenous FSH drug calculated by equation one (EXP) (g + h age + i basal FSH + j LN [ basal AMH ] + k basal AFC)
Wherein g is selected from any value of-3.167587 to-2.751518, preferably-2.959552;
h is selected from any value of-0.025951 to-0.016355, preferably-0.021153;
i is selected from any value of-0.048143 to-0.025727, preferably-0.036935;
j is any value selected from 0.5174476-0.6075545, preferably 0.5625011;
k is any value of 0.0241595-0.0365579, preferably 0.0303587.
36. The method of item 35, wherein the initial dose of the exogenous FSH drug to be administered to the subject is calculated using equation three based on the first calculated predicted resulting egg count (predicted NROs) and the second calculated ratio, wherein equation three is:
initial dose of exogenous FSH drug-Round (predicted NROs calculated by formula one/predicted ovarian sensitivity calculated by formula two, 0).
37. The method of any one of items 23 to 28, wherein,
acquiring data of age, basal anti-mullerian hormone (AMH) level, basal Antral Follicle Count (AFC), inhibin B level dynamics (Δ INHB) of the subject in a data acquisition step;
in the step of calculating the exogenous FSH medicament dose, the data acquired by the data acquisition module are calculated for the first time, so that the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation-promoting period is calculated; performing a second calculation on the data acquired by the data acquisition module, thereby calculating the ratio of the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation-promoting cycle to the adjusted dose of the exogenous FSH medicament, namely predicting the ovarian sensitivity; an adjusted dose of exogenous FSH drug to be administered to the subject is calculated based on the first calculated predicted egg counts (predicted NROs) and the second calculated ratio.
38. The method of item 37, wherein,
in the exogenous FSH drug dose calculation step, a formula iv for calculating the predicted number of eggs obtained from the subject (predicted NROs) is stored in advance based on the age of the patient who had received ovulation induction treatment using the standard GnRH antagonist regimen, the basal anti-mullerian hormone (AMH) level, the basal sinus follicle count (AFC), the dynamic change in inhibin B level (Δ INHB), and the actual number of eggs obtained from the existing database.
39. The method of item 38, wherein,
in the exogenous FSH drug dose calculation step, the fourth formula is a calculation formula obtained by fitting the data of the age, the basic anti-mullerian hormone (AMH) level, the basic Antral Follicle Count (AFC), the inhibin B level dynamic change (delta INHB) and the actual egg acquisition number (fate variable) of the patient who is subjected to ovulation induction treatment by the standard GnRH antagonist scheme in the existing database by using fate variable negative binomial distribution;
the fourth equation is capable of calculating predicted harvested eggs (predicted NROs) of the subject using the age data of the subject, the basal anti-mullerian hormone (AMH) level data of the subject, the basal sinus follicle count (AFC) data of the subject, and the inhibin B level dynamics (Δ INHB) data of the subject acquired by the data acquisition module.
40. The method of item 39, wherein the formula four is:
predicting NROs ═ EXP (w + m age + n LN [ basal AMH ] + o LN [ Δ INHB ] + p LN [ basal AFC ]);
wherein w is any value selected from-0.447201-0.9161863, preferably 0.2344927;
m is any value of-0.017165-0.0039328, preferably-0.006616;
n is any value of 0.1318094-0.3113979, preferably 0.2216036;
o is any value of 0.1901643-0.3850919, preferably 0.2876281;
p is any value of 0.0541966-0.2338079, preferably 0.1440023.
41. The method of item 40, wherein,
in the exogenous FSH drug dose calculation step, a fifth formula for calculating the predicted ovarian sensitivity of the subject, i.e., the ratio of the predicted number of eggs obtained (predicted NROs) to the adjusted dose of the exogenous FSH drug, which is obtained by fitting data of the ratio of the predicted number of eggs obtained (predicted NROs) calculated by the fourth formula to the average daily dose of the exogenous FSH drug used by the patient, based on the age of the patient who had received ovulation-promoting treatment with the standard GnRH antagonist regimen, the basal anti-mullerian hormone (AMH) level, the basal sinus follicle count (AFC), the dynamic change in inhibin B level (Δ INHB), and the fourth formula, is stored in advance;
wherein the average daily dose of the exogenous FSH drug administered to the patient is the ratio of the total dose of the exogenous FSH drug administered to the patient during the past ovulation induction treatment with the standard GnRH antagonist regimen to the number of days the exogenous FSH drug was administered.
42. The method of item 41, wherein,
in the exogenous FSH drug dose calculation step, the formula five can calculate the predicted ovarian sensitivity of the subject, i.e., the ratio of the predicted number of eggs obtained (predicted NROs) to the adjusted dose of exogenous FSH drug administered to the subject, using the age data of the subject, the basal anti-mullerian hormone (AMH) level data of the subject, the basal sinus follicle count (AFC) data of the subject, and the dynamictic change in INHB level (Δ INHB) data of the subject, which are obtained by the data acquisition module.
43. The method of item 41 or 42, wherein the formula five is:
predicted ovarian sensitivity in subjects, i.e., predicted NROs/exogenous FSH drug adjusted dose calculated by equation four (EXP (q + r age + s LN [ basal AMH ] + t basal AFC + u LN [ Δ INHB ])
Wherein q is any value selected from-5.63461 to-5.108612, preferably-5.371611;
r is selected from any value of-0.0264 to-0.015183, preferably-0.020792;
s is any value of 0.2696292-0.3684551, preferably 0.3190421;
t is any value of 0.0273504-0.0399372, preferably 0.0336438;
u is any value of 0.3327566-0.3940448, preferably 0.3634007.
44. The method of item 43, wherein the adjusted dose of exogenous FSH drug to be administered to the subject is calculated using equation six based on the first calculated predicted egg counts (predicted NROs) and the second calculated ratio, wherein equation six is:
exogenous FSH drug adjusted dose-Round (predicted NROs calculated by equation four/predicted ovarian sensitivity calculated by equation five, 0).
ADVANTAGEOUS EFFECTS OF INVENTION
The system or method of the application, through establishing a model for predicting the number of mature oocytes obtained by a subject in an ovulation induction cycle based on a plurality of basic indexes at first, and then establishing a model for predicting ovarian sensitivity, only one unknown variable of the exogenous FSH drug dosage is included in the result variables of ovarian sensitivity, in this case, the dosage can be predicted, and the model R is 2 Above 0.9, this means that the algorithm of the present application can account for more than 90% of ovarian sensitivity, which to our knowledge is the best model to predict ovarian sensitivity worldwide, and its use may change COS clinical routine in the near future, which will help improve pregnancy outcome, reduce the incidence of OHSS and reduce costs during COS, and is expected to greatly improve ART treatment, especially to improve ART physician treatment homogeneity, while accelerating physicians' learning curves. The method or system of the application can realize the prediction of the initial dose and the adjusted dose according to the basic index. The methods or systems contemplated herein may be used to guide the initial and adjusted doses of exogenous FSH used by an individual during ovulation induction.
Drawings
Various other advantages and benefits of the present application will become apparent to those of ordinary skill in the art upon reading the following detailed description of the preferred embodiments. The drawings are only for purposes of illustrating the preferred embodiments and are not to be construed as limiting the application. It is obvious that the drawings described below are only some embodiments of the application, and that for a person skilled in the art, other drawings can be derived from them without inventive effort. Moreover, in all the figures, like parts are denoted by like reference numerals.
FIG. 1A is a histogram of the skewness of the model two fitting result variables.
FIG. 1B is a normal distribution plot of the model two fit result variables.
FIG. 1C is a graph of the non-linear relationship of AMH to the resulting variable.
Fig. 2A and 2B are diagrams of model two-independent variable screening processes.
FIG. 2C is a diagram of the results of the contribution evaluation of the four predictors in model two.
FIG. 2D is a scatter plot of the predicted effect of model two in the training set.
FIG. 2E is a scatter plot of the predicted effect of model two in the validation set.
FIG. 2F is a diagram of the residual prediction effect of model II in the training set.
Fig. 2G is a residual prediction effect diagram of model two in the validation set.
Fig. 3A and 3B are graphs of model four-independent variable screening processes.
FIG. 3C is a graph of the results of the contribution evaluation of the four predictors in model four.
FIG. 3D is a scatter plot of the predicted effect of model four in the training set.
FIG. 3E is a scatter plot of the predicted effect of model four in the validation set.
Fig. 3F is a diagram of the residual prediction effect of model four in the training set.
Fig. 3G is a diagram of the prediction effect residual of model four in the validation set.
Detailed Description
Specific embodiments of the present application will be described in more detail below with reference to the accompanying drawings. While specific embodiments of the present application are shown in the drawings, it should be understood that the present application may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art.
It is to be understood that throughout the specification and claims, the terms "including" and "comprising" are used in an open-ended fashion, and thus should be interpreted to mean "including, but not limited to. The description which follows is a preferred embodiment of the present application, but is made for the purpose of illustrating the general principles of the application and not for the purpose of limiting the scope of the application. The protection scope of the present application shall be subject to the definitions of the appended claims.
Variable types: in statistics, variable types can be divided into quantitative variables and qualitative variables (also called categorical variables).
The quantitative variables are variables for describing the number and quantity of things, and can be classified into a continuous type and a discrete type. The continuous variable refers to a variable which can be arbitrarily valued in a certain interval, and the value is continuous and can have decimal points. For example, blood pressure, blood sugar level, height, weight, chest circumference, etc. measured by a human body are continuous variables, and the values thereof can be obtained only by a measurement or measurement method. A discrete variable is a variable whose value can only be in natural or integer units. For example, pain scores, lesion metastasis counts, egg counts, etc. are positive numbers only, and decimal points are not available, and the numerical values of these variables are generally obtained by numerical methods.
The variable types are not invariable and conversion between the various types of variables is possible depending on the needs of the study. For example, the hemoglobin (g/L) is a primary numerical variable, and if the hemoglobin is divided into two categories according to the normal hemoglobin and the low hemoglobin, the two categories can be analyzed according to the two categories; if the grade is five according to severe anemia, moderate anemia, mild anemia, normal and hemoglobin increase, the grade data can be analyzed. The classifier data may also be quantified, e.g., the patient's nausea response may be expressed as 0, 1, 2, 3, and may be analyzed as numerical variable data (quantitative data).
The outcome variable, also called outcome variable, for short, outcome, refers to the expected outcome event that will occur during follow-up observations, i.e., the event that the researcher wishes to follow-up the observations.
The cause variable refers to a factor or condition that is actively manipulated by a researcher to cause a change in the outcome variable, and thus the cause variable is considered to be the cause of the outcome variable.
Poisson distribution (Poisson distribution) is a discrete probability distribution (discrete probability distribution) that is commonly found in statistics and probability. The poisson distribution is suitable for describing the number of times a random event occurs per unit time (or space). Such as the number of disease cases occurring in a certain fixed space and time, the number of times a certain disease recurs, the number of sites of metastasis of a certain lesion, the number of vomits of a certain patient, and the like.
The negative binomial distribution is a statistically discrete probability distribution. A distribution called negative binomial that satisfies the following condition: the experiment comprises a series of independent experiments, each experiment has success and failure results, the success probability is constant, the experiment lasts until r times of success, and r is a positive integer. The negative binomial distribution, similar to the Poisson distribution, can also be used to describe the relative frequency of a rare event in space per unit time. It differs from the Poisson distribution in that the Poisson distribution can only be used to describe independent events, while the negative binomial distribution is often used to describe aggregate events, such as the distribution of oncomelania in soil, the distribution of an infectious disease, etc. Generally, if the mean value of the counting data is larger than the variance, the Poisson distribution is not good in fitting effect, and the negative binomial distribution can be considered.
A normal distribution is a statistical probability distribution, which is a distribution of continuous random variables with two parameters μ and σ 2, the first parameter μ being the mean of the random variables distributed from the normal, and the second parameter σ 2 being the variance of the random variables, so the normal distribution is denoted as N (μ, σ 2). The probability law of the random variables following normal distribution is that the probability of taking the values with adjacent mu is large, and the probability of taking the values with higher mu and farther mu is smaller; the smaller the distribution, the more concentrated the distribution near μ, and the larger the distribution, the more dispersed. The normally distributed density function is characterized in that: with respect to μ symmetry, a maximum is reached at μ, a value of 0 at positive (negative) infinity, and an inflection point at μ ±. The shape of the image is high in the middle and low on two sides, and the image is a bell-shaped curve located above the x axis. When μ is 0 and σ 2 is 1, it is called a normal distribution and is denoted as N (0, 1).
Herein, anti-mullerian hormone (AMH) refers to a hormone secreted by the granulosa cells of ovarian small follicles, and female babies at the fetal stage start to make AMH, and the larger the number of small follicles in the ovaries, the higher the concentration of AMH; on the contrary, when the follicles are gradually consumed with age and various factors, the AMH concentration is also decreased, and the closer to the menopause, the AMH tends to be 0.
In this context, Follicle Stimulating Hormone (FSH) refers to a hormone secreted by the basophils of the anterior pituitary, and is composed of glycoproteins, which primarily function to promote follicle maturation. FSH promotes proliferative differentiation of follicular granular layer cells and promotes overall ovarian growth. And acting on the seminal tubules of testis to promote spermatogenesis. FSH is secreted in the human body in pulses, which vary in women with the menstrual cycle. The determination of FSH in serum has important significance for diagnosing and treating infertility and endocrine diseases, such as understanding pituitary endocrine function, indirectly understanding ovarian functional state, evaluating ovarian reserve and ovarian reactivity, and making ovulation-promoting drug dosage.
Recently, serotonin B levels have been considered as markers of follicular development. Inhibin B participates in the selection of follicles in the normal menstrual cycle through endocrine and paracrine actions, promoting the growth of follicles. One of the effects of inhibin B is to down-regulate FSH secretion in the mid-follicular phase of the natural menstrual cycle. It also exerts a paracrine effect, stimulating oocyst membrane cells to produce androgens and LH. The secretion of inhibin B reaches a peak in the early follicular phase, with a diameter of 10-12 mm. Inhibin B at day 5 (early follicular phase) has been shown to be an excellent marker of poor ovarian response and live birth compared to basal markers. Inhibin B is produced predominantly by FSH-sensitive follicles, and administration of exogenous FSH results in an increase in the number of follicles that grow. In line with this, the present inventors have found that the dynamic change in inhibin B levels (Δ INHB), i.e. the difference between the inhibin B concentration at day 6 and the inhibin B concentration at day 2 of the ovulation cycle, is the best marker for predicting the adjusted dosage of FSH drug.
Luteinizing Hormone (LH), a glycoprotein gonadotropin secreted by adenohypophysis cells, promotes the conversion of cholesterol into sex hormones in gonadal cells. In women, it works in conjunction with Follicle Stimulating Hormone (FSH) to promote follicular maturation, secretion of estrogen, ovulation, and production and maintenance of the corpus luteum, secretion of progestin and estrogen. For men, luteinizing hormone promotes synthesis and release of testosterone by leydig cells. LH levels refer to the LH concentration in the venous blood serum sample of female subjects during 2-4 days of menstruation.
Foundation E 2 Levels refer to estradiol levels, which is a steroidal estrogen. The alpha type and the beta type have two types, and the alpha type has strong physiological action. It has a strong sex hormone action, so it or its ester is considered to be actually the most important sex hormone secreted by the ovary. In the present application, the detection of a basal estradiol level is the concentration of estradiol in a venous blood serum sample of a female subject taken 2-4 days per month.
BMI is an important international standard for measuring the obesity and health of human body, and is mainly used for statistical analysis. The determination of the degree of obesity cannot be made using the absolute value of weight, which is naturally related to height. Therefore, BMI obtains a relatively objective parameter through two values of the weight and the height of a human body, and measures the body mass by using the range of the parameter. BMI is the square of weight/height (international units kg/m) 2 )。
In this context, Antral Follicle Count (AFC) refers to the number of all visible follicles with a diameter of 2-10mm in both ovaries on a 2-4 day menstrual period. AFC can be measured and counted by ultrasound on follicles.
Ovarian sensitivity refers to the ratio of the number of mature oocytes (NROs) obtained to the dose of exogenous FSH drug.
To address the lack of individualized guidance in predicting the dosage of exogenous FSH drugs in the prior art, the present application provides a system for predicting the dosage of exogenous Follicle Stimulating Hormone (FSH) drugs used by a subject to control the sexual ovarian stimulation cycle when the subject is undergoing ovulation induction treatment with a standard GnRH antagonist regimen, comprising: a data acquisition module for acquiring data of age, basal anti-mullerian hormone (AMH) level, basal Follicle Stimulating Hormone (FSH) level or inhibin B level dynamic change (Δ INHB), basal sinus follicle count (AFC) of a subject; and an exogenous Follicle Stimulating Hormone (FSH) drug dose calculation module for: calculating the data acquired by the data acquisition module for the first time so as to calculate the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation induction period; performing a second calculation on the data acquired by the data acquisition module, thereby calculating the ratio of the predicted number of eggs (predicted NROs) acquired by the subject during the ovulation-promoting cycle to the dose of the exogenous FSH drug given to the subject during the ovulation-promoting cycle, namely predicting the ovarian sensitivity; calculating an exogenous FSH drug dose to be administered to the subject based on the first calculated predicted egg counts (predicted NROs) and the ratio.
The system of the application can realize the prediction of exogenous FSH medicament dosage by firstly establishing a model for predicting the number of mature oocytes obtained by a subject in an ovulation induction cycle based on a plurality of basic indexes and then establishing a model for predicting ovarian sensitivity so that only the dosage of exogenous FSH medicament is an unknown variable in the result variables of the ovarian sensitivity, wherein the model R is a model R 2 Is more than 0.9 and is far superior to the model of Lar Marca and the like, and is further optimized for the model in the prior art. The system of the present application helps to improve pregnancy outcome, reduce the incidence of OHSS and reduce costs during COS, and is expected to greatly improve the therapeutic effect of ART.
The subject is to be treated with standard GnRH antagonist protocol for ovulation induction, and the number of eggs obtained (NROs) from the subject is the number of mature oocytes with a diameter of 10mm or more, preferably 15mm or more obtained after inducing follicle maturation by hCG injection after 1-2 dominant follicles in the ovarian stimulation process after the subject receives ovulation induction.
In one embodiment, among others, the standard GnRH antagonist ovarian stimulation protocol described herein is performed as follows: exogenous FSH (human recombinant FSH, abbreviated as human rFSH) (e.g., Gonal-Falfa [ Merck Serono, Germany)]，Puregon beta[MSD，USA],Urofollitropin[Livzon Pharmaceutical Group Inc.，China]Or Menotropphins [ Livzon Pharmaceutical ]]Group Inc.，China]) Dosing began on day 2 of the menstrual cycle. The initial dose of human rFSH is selected based on age, basal AMH level, basal FSH level, basal AFC level, and BMI. Size of the growing follicles observed on ultrasound andquantification and monitoring of serum E during ovarian stimulation 2 The levels were further adjusted for rFSH dose. GnRH antagonist treatment was started when the diameter of the growing follicles reached 10-12 mm. hCG (Chonogonodotropinalfa, Merck Serono) was injected at a dose of 5000-10000 IU to trigger final oocyte maturation when at least two dominant follicles were observed to be over 18mm in diameter by ultrasound. Oocyte retrieval was performed 36-38 hours after hCG administration. Transferring one or two embryos or performing embryo cryopreservation. The subject was then provided luteal phase progesterone support (progesterone vaginal gel, Merck Serono).
In a specific embodiment of the present application, the subject to which the systems and methods are directed is a subject undergoing ovulation-promoting treatment with a standard GnRH antagonist regimen as described above.
Those skilled in the art will appreciate that there are many factors that generally affect the number of oocytes harvested from a subject, such as the BMI index, the duration of infertility, the number of previous in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) attempts, the serum basal E 2 Levels, FSH and LH levels, serum AMH levels, left and right ovarian AFCs, first, second, third, fourth and fifth causes of infertility, conventional or mild ovarian stimulation cycles, ovarian stimulation type/COS regimen, initial and total doses of rFSH, duration of rFSH treatment (days), name of rFSH, endometrial thickness on the day of human chorionic gonadotropin (hCG) triggering, etc. in this application, the inventors of the present application finally confirmed four important parameters of age, basal anti-mullerian hormone (AMH) level, basal Follicle Stimulating Hormone (FSH) level and basal sinus number (AFC) of the subject by screening of various indices to calculate NROs of the subject.
The data acquisition module is not limited to any specific one, and may be any module that can acquire data on the age, basal anti-mullerian hormone (AMH) level, basal Follicle Stimulating Hormone (FSH) level, or inhibin B level dynamics (Δ INHB), and basal Antral Follicle Count (AFC) of a subject. Wherein, in particular, the basal anti-mullerian hormone (AMH) level obtained by the data acquisition module refers to the anti-mullerian hormone concentration in venous blood of the female subject at any time point during the menstrual period; the basal Follicle Stimulating Hormone (FSH) level obtained by the data acquisition module is the follicle stimulating hormone concentration in venous blood of a female subject on day 2 of menses; the basic Antral Follicle Count (AFC) obtained by the data acquisition module refers to the number of all visible follicles with the diameter of 2-10mm in two ovaries of a female subject on day 2 of menstruation, wherein the number of the follicles is counted by a vaginal type-B ultrasonic scanner; the inhibin B level dynamic change (Δ INHB) obtained by the data acquisition module is the inhibin B level dynamic change (Δ INHB) in the early period of ovulation induction treatment, and preferably is the difference between the serum inhibin B concentration at day 6 of menstruation and the inhibin B concentration in venous blood at day 2 of menstruation of a female subject receiving a GnRH antagonist regimen for the ovulation induction treatment cycle. Based on the subject who needs to predict the number of oocytes obtained during ovarian stimulation, the data given above can be taken for the prediction of the number of eggs obtained based on the system of the present application.
Herein, the data obtained from the data acquisition module is subjected to a first calculation and a second calculation by using the exogenous FSH dose calculation module, so as to calculate the ratio of the predicted number of obtained eggs (predicted NROs) obtained by the subject during the ovulation-promoting cycle to the dose of the exogenous FSH drug administered to the subject during the ovulation-promoting cycle. The system of the present application can predict the initial and adjusted doses of exogenous FSH drug administered to a subject as recommended during a controlled ovarian stimulation cycle.
In the above system, the brand of the exogenous follicle stimulating hormone drug is not limited, and may be, for example, Gonal-F, Puregon, urofollitropin for injection, HMG, etc., and the brand of FSH does not affect the accuracy of the system in predicting the initial dose and the adjusted dose.
In one embodiment, the system of the present application is a system for predicting an initial dose of an exogenous FSH drug to be administered to a subject during a controlled ovarian stimulation cycle, wherein the data acquisition module is configured to obtain data on the age, basal anti-mullerian hormone (AMH) level, basal Follicle Stimulating Hormone (FSH) level, basal sinus follicle count (AFC) of the subject; the exogenous FSH drug dose calculation module is configured to: calculating the data acquired by the data acquisition module for the first time so as to calculate the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation induction period; performing a second calculation on the data acquired by the data acquisition module, thereby calculating the ratio of the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation induction cycle to the initial dose of the exogenous FSH medicament, namely predicting the ovarian sensitivity; calculating an initial dose of exogenous FSH drug to be administered to the subject based on the first calculated predicted egg counts (predicted NROs) and the second calculated ratio.
First, it should be understood that the module is pre-stored with data based on the age of the patient undergoing ovulation induction treatment with a standard GnRH antagonist regimen in an existing database, the basal anti-mullerian hormone (AMH) level, the basal Follicle Stimulating Hormone (FSH) level, the basal sinus follicle count (AFC), the number of oocytes actually detected to be harvested (actual number of eggs harvested), and a formula one for calculating the predicted number of eggs harvested (predicted NROs) of the subject based on the pre-stored data of the patient and a negative binomial distribution fit. By using a pre-stored formula I, calculation can be performed for any subject, so that the number of mature oocytes (NROs) obtained by the subject is predicted, and the predicted number of obtained oocytes (predicted NROs) is obtained.
In addition, it should also be understood that the module also stores in advance data based on the age of the patient undergoing ovulation induction treatment with the standard GnRH antagonist regimen in the existing database, the basal anti-mullerian hormone (AMH) level, the basal Follicle Stimulating Hormone (FSH) level, the basal sinus follicle count (AFC), the ratio of the predicted number of eggs obtained (predicted NROs) calculated by formula one to the average daily dose of exogenous FSH drug administered to said patient, and a formula two for calculating the predicted ovarian sensitivity of the subject, i.e., the ratio of the predicted number of eggs obtained (predicted NROs) of the subject to the initial dose of exogenous FSH drug administered to the subject, fitted to these data. With the pre-stored formula two, the calculation can be performed for any subject.
In the present application, the average daily dose of the exogenous FSH drug administered to the patient is the ratio of the total dose of the exogenous FSH drug administered to the patient during the ovulation induction treatment with the standard GnRH antagonist regimen to the number of days the exogenous FSH drug is administered.
Specifically, the pre-stored formula is fit to pre-stored data based on the age, basal anti-mullerian hormone (AMH) level, basal Follicle Stimulating Hormone (FSH) level, basal Antral Follicle Count (AFC), and actual detected number of oocytes retrieved for the ovulation-promoting treatment patient who received the standard GnRH antagonist regimen in the existing database. The second pre-stored formula is fitted with pre-stored data based on the ratio of the age of a patient undergoing ovulation induction therapy with a standard GnRH antagonist regimen in an existing database, the basal anti-mullerian hormone (AMH) level, the basal Follicle Stimulating Hormone (FSH) level, the basal sinus follicle count (AFC), the predicted number of eggs obtained (predicted NROs) calculated by the first formula, and the average daily dose of exogenous FSH drug administered to said patient.
In the calculating, the pre-stored formula is a formula for calculating predicted harvested egg numbers (predicted NROs) of the subject using age data of the subject, basal anti-mullerian hormone (AMH) level data of the subject, basal Follicle Stimulating Hormone (FSH) level data of the subject, and basal sinus follicle count (AFC) data of the subject acquired by the data acquisition module. The second pre-stored formula is a formula for calculating a ratio of predicted harvested eggs (predicted NROs) of the subject to an initial dose of the exogenous FSH drug administered to the subject using the age data of the subject, the basal anti-mullerian hormone (AMH) level data of the subject, the basal Follicle Stimulating Hormone (FSH) level data of the subject, and the basal sinus follicle count (AFC) data of the subject obtained by the data acquisition module.
Further, the inventors of the present application constructed a specific formula one for predicting NROs:
predicting NROs ═ EXP (a + b age + c basal FSH + d LN [ basal AMH ] + f LN [ basal AFC ]);
further, in the formula one,
a is any value of 1.5576128-2.6037078, preferably 2.0806603;
b is any value of-0.019097-0.0044064, preferably-0.007345;
c is selected from any value of-0.045234 to-0.004054, preferably-0.024644;
d is any value of 0.348168-0.4948875, preferably 0.4215277;
f is any value of 0.0415663-0.2566199, preferably 0.1490931.
The inventors of the present application constructed formula two for predicting the initial dose of exogenous FSH drug based on formula one:
predicted ovarian sensitivity in subjects, i.e., the predicted NROs/exogenous FSH drug initial dose calculated by equation one (EXP (g + h age + i basal FSH + j LN [ basal AMH ] + k basal AFC);
further, in the formula two,
g is selected from any value of-3.167587 to-2.751518, preferably-2.959552;
h is selected from any value of-0.025951 to-0.016355, preferably-0.021153;
i is selected from any value of-0.048143 to-0.025727, preferably-0.036935;
j is any value of 0.5174476-0.6075545, preferably 0.5625011;
k is any value of 0.0241595-0.0365579, preferably 0.0303587.
In the above system, the initial dose of exogenous FSH drug to be administered to the subject is calculated by dividing the predicted NROs calculated in equation one by the ratio calculated in equation two.
In the above system, the initial dose of exogenous FSH drug administered to the subject may be calculated using equation three:
initial dose of exogenous FSH drug-Round (predicted NROs calculated by formula one/predicted ovarian sensitivity calculated by formula two, 0).
In one embodiment, the system of the present application is a system for predicting an adjusted dosage of an exogenous FSH drug to a subject during a controlled ovarian stimulation cycle, wherein the data acquisition module is configured to acquire data on the subject's age, basal anti-mullerian hormone (AMH) level, basal sinus follicle count (AFC), and dynamic change in inhibin B level (Δ INHB); the exogenous FSH drug dose calculation module is configured to: calculating the data acquired by the data acquisition module for the first time so as to calculate the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation induction period; performing a second calculation on the data acquired by the data acquisition module, thereby calculating the ratio of the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation-promoting cycle to the adjusted dose of the exogenous FSH medicament, namely predicting the ovarian sensitivity; an adjusted dose of exogenous FSH drug to be administered to the subject is calculated based on the first calculated predicted egg counts (predicted NROs) and the second calculated ratio.
First, it should be understood that the module has previously stored therein data based on the age of the patient undergoing ovulation induction treatment with a standard GnRH antagonist regimen in an existing database, the basal anti-mullerian hormone (AMH) level, the inhibin B level dynamic change (Δ INHB), the basal sinus follicle count (AFC), the actual number of eggs obtained, and a fourth formula for calculating the predicted number of eggs obtained (predicted NROs) for the subject based on the pre-stored data for the patient and a negative binomial distribution fit. Using a pre-stored formula four, calculations can be performed for any subject to calculate predicted number of eggs (predicted NROs).
In addition, it will also be appreciated that data for the ratio of the predicted number of eggs obtained (predicted NROs) calculated from equation four to the average daily dose of exogenous FSH drug administered to the patient based on the age, the basal anti-mullerian hormone (AMH) level, the inhibin B level dynamics (Δ INHB), the basal sinus follicle count (AFC), and the predicted number of eggs obtained (predicted NROs) for the patient who has received standard GnRH antagonist regimen ovulation treatment in an existing database, and equation five for calculating the predicted ovarian sensitivity of the subject based on these data fit, i.e., the ratio of the predicted number of eggs obtained (predicted NROs) for the subject to the adjusted dose of exogenous FSH drug administered to the subject, are also prestored in the module. With the formula five pre-stored, the calculation can be performed for any subject.
In the present application, the average daily dose of the exogenous FSH drug administered to the patient is the ratio of the total dose of the exogenous FSH drug administered to the patient during the ovulation induction treatment with the standard GnRH antagonist regimen to the number of days the exogenous FSH drug is administered.
Specifically, the fourth pre-stored formula is fitted with pre-stored data based on the age, basal anti-mullerian hormone (AMH) level, inhibin B level dynamics (Δ INHB), basal sinus follicle count (AFC), and actual number of eggs obtained from patients who received standard GnRH antagonist regimens from existing databases. The fifth pre-stored formula is fitted with pre-stored data based on the ratio of the predicted number of eggs obtained (predicted NROs) calculated from the fourth formula to the average daily dose of exogenous FSH drug administered to the patient for ovulation induction treatment of patients receiving a standard GnRH antagonist regimen in an existing database, the basal anti-mullerian hormone (AMH) level, the dynamic change in inhibin B level (Δ INHB), the basal sinus follicle count (AFC).
In calculating, the fourth pre-stored formula is a formula for calculating predicted number of eggs obtained (predicted NROs) for the subject using the age data of the subject, the basal anti-mullerian hormone (AMH) level data of the subject, the inhibin B level dynamics (Δ INHB) data of the subject, and the basal sinus follicle count (AFC) data of the subject obtained by the data acquisition module. The fifth pre-stored formula is a formula for calculating a ratio of predicted harvested eggs (predicted NROs) of the subject to an adjusted dose of the exogenous FSH drug administered to the subject using the age data of the subject, the basal anti-mullerian hormone (AMH) level data of the subject, the statin B level dynamics (Δ INHB) data of the subject, and the basal sinus follicle count (AFC) data of the subject acquired by the data acquisition module.
Further, the inventors of the present application constructed a specific formula four for predicting NROs:
predicting NROs ═ EXP (w + m age + n LN [ basal AMH ] + o LN [ Δ INHB ] + p LN [ basal AFC ]);
further, in the formula four,
w is any value of-0.447201-0.9161863, preferably 0.2344927;
m is any value of-0.017165-0.0039328, preferably-0.006616;
n is any value of 0.1318094-0.3113979, preferably 0.2216036;
o is any value of 0.1901643-0.3850919, preferably 0.2876281;
p is any value of 0.0541966-0.2338079, preferably 0.1440023.
The inventors of the present application constructed formula five for predicting the adjusted dose of the exogenous FSH drug on the basis of formula four:
predicted ovarian sensitivity in subjects, i.e., the predicted NROs/exogenous FSH drug adjusted dose calculated by equation four, EXP (q + r age + s LN [ basal AMH ] + t basal AFC + u LN [ Δ INHB ]);
further, in the formula five,
q is any value selected from-5.63461 to-5.108612, preferably-5.371611;
r is selected from any value of-0.0264 to-0.015183, preferably-0.020792;
s is any value of 0.2696292-0.3684551, preferably 0.3190421;
t is any value of 0.0273504-0.0399372, preferably 0.0336438;
u is any value of 0.3327566-0.3940448, preferably 0.3634007.
In the above system, the adjusted dose of the exogenous FSH drug to be administered to the subject can be calculated by dividing the predicted NROs calculated by equation four by the ratio calculated by equation five.
In the above system, the adjusted dose of exogenous FSH drug to be administered to the subject may be calculated using equation six, which is:
exogenous FSH drug adjusted dose-Round (predicted NROs calculated by equation four/predicted ovarian sensitivity calculated by equation five, 0).
To address the problem of the prior art of lacking individualized guidance for predicting the dose of exogenous FSH medication, the present application further provides a method for predicting the dose of exogenous FSH medication administered to a subject during a controlled ovarian stimulation cycle, comprising:
a data acquisition step: obtaining data on age, basal anti-mullerian hormone (AMH) level, basal Follicle Stimulating Hormone (FSH) level or dynamic change in inhibin B level (Δ INHB), basal Antral Follicle Count (AFC) of the subject; and
calculating the dosage of the exogenous follicle stimulating hormone: calculating the data acquired in the data acquisition step for the first time, thereby calculating the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation induction period; performing a second calculation on the acquired data in the data acquisition module, thereby calculating the ratio of the predicted number of acquired eggs (predicted NROs) of the subject in the ovulation-promoting cycle to the initial dose of the exogenous FSH medicament administered to the subject in the ovulation-promoting cycle, namely predicting the ovarian sensitivity; calculating an exogenous FSH drug dose to be administered to the subject based on the first calculated predicted egg counts (predicted NROs) and the ratio.
In the above method, the subject is a subject to be treated with standard GnRH antagonist protocol for ovulation induction, and the number of mature oocytes in the subject is 10mm or more, preferably 15mm or more, obtained after inducing follicle maturation by hCG injection after 1-2 dominant follicles in the ovarian stimulation process after the subject is treated with ovulation induction.
In the above method, in the data collecting step, the obtained basal anti-mullerian hormone (AMH) level refers to the anti-mullerian hormone concentration in venous blood of the subject at any time point during the menstruation period before ovulation induction treatment.
In the above method, in the data collecting step, the obtained basal Follicle Stimulating Hormone (FSH) level refers to the follicle stimulating hormone concentration in venous blood on day 2 of menstruation before ovulation induction treatment in the female subject.
In the above method, in the data collection step, the obtained basal Antral Follicle Count (AFC) is the number of all visible follicles with a diameter of 2 to 10mm in both ovaries of a female subject on day 2 of menstruation, in terms of vaginal B-ultrasound count.
In the above method, in the data collecting step, the obtained dynamic change in inhibin B level (Δ INHB) refers to the dynamic change in inhibin B level (Δ INHB) at the early stage of ovulation induction treatment, and preferably is the difference between the concentration of serotonin B at day 6 of menstruation and the concentration of inhibin B in venous blood at day 2 of menstruation in a female subject undergoing a GnRH antagonist regimen for ovulation induction treatment. A
In the above method, the brand of the exogenous follicle stimulating hormone drug is not limited, and may be, for example, Gonal-F, Puregon, urofollitropin for injection, HMG, etc., and the brand of FSH does not affect the accuracy of the method for predicting the initial dose and the adjusted dose.
In one embodiment, the method of the present application is a method of predicting an initial dose of an exogenous FSH drug to be administered to a subject during a controlled ovarian stimulation cycle, wherein, in the above method, data is obtained for the age, basal anti-mullerian hormone (AMH) level, basal Follicle Stimulating Hormone (FSH) level, basal sinus follicle count (AFC) of the subject during a data collection step; in the step of calculating the exogenous FSH medicament dose, the data acquired by the data acquisition module are calculated for the first time, so that the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation-promoting period is calculated; performing a second calculation on the data acquired by the data acquisition module, thereby calculating the ratio of the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation induction cycle to the initial dose of the exogenous FSH medicament, namely predicting the ovarian sensitivity; an initial dose of exogenous FSH drug to be administered to the subject is calculated based on the first calculated predicted egg counts (predicted NROs) and the second calculated ratio.
First, it should be understood that, in the above method, in the exogenous FSH drug dose calculation step, data based on the age of a patient who has received ovulation induction treatment with a standard GnRH antagonist regimen in an existing database, the basal anti-mullerian hormone (AMH) level, the basal Follicle Stimulating Hormone (FSH) level, the basal sinus follicle count (AFC), the actually detected number of oocytes harvested (actual number of oocytes harvested), and a formula one for calculating the predicted number of oocytes harvested (predicted NROs) of the subject, which is fitted based on the pre-stored data of the patient and the negative binomial distribution, are previously stored. By using a pre-stored formula I, calculation can be performed for any subject, so that the number of mature oocytes (NROs) obtained by the subject is predicted, and the predicted number of obtained oocytes (predicted NROs) is obtained.
Furthermore, it should be understood that, in the above method, in the exogenous FSH drug dose calculation step, data of the ratio of the predicted number of eggs obtained (predicted NROs) calculated by the formula one to the average daily dose of exogenous FSH drugs used by the patient based on the age of the patient who had received ovulation induction treatment with the standard GnRH antagonist regimen in the existing database, the basal anti-mullerian hormone (AMH) level, the basal Follicle Stimulating Hormone (FSH) level, the basal sinus follicle count (AFC), and the predicted ovarian sensitivity of the subject, i.e., the ratio of the predicted number of eggs obtained (predicted NROs) of the subject to the initial dose of exogenous FSH drugs administered to the subject, are also previously stored. With the pre-stored formula two, the calculation can be performed for any subject.
In the present application, the average daily dose of the exogenous FSH drug administered to the patient is the ratio of the total dose of the exogenous FSH drug administered to the patient during the ovulation induction treatment with the standard GnRH antagonist regimen to the number of days the exogenous FSH drug is administered.
Specifically, the pre-stored formula is fitted with pre-stored data based on the age, basal anti-mullerian hormone (AMH) level, basal Follicle Stimulating Hormone (FSH) level, basal sinus follicle count (AFC), and actual detected number of oocytes harvested from patients who have received standard GnRH antagonist regimens from existing databases. The second pre-stored formula is fitted with pre-stored data based on the ratio of the age of a patient undergoing ovulation induction therapy with a standard GnRH antagonist regimen in an existing database, the basal anti-mullerian hormone (AMH) level, the basal Follicle Stimulating Hormone (FSH) level, the basal sinus follicle count (AFC), the predicted number of eggs obtained (predicted NROs) calculated by the first formula, and the average daily dose of exogenous FSH drug administered to said patient.
In the calculating, the prestored formula is a formula for calculating predicted harvested egg numbers (predicted NROs) of the subject using the age data of the subject, the basal anti-mullerian hormone (AMH) level data of the subject, the basal Follicle Stimulating Hormone (FSH) level data of the subject, and the basal sinus follicle count (AFC) data of the subject acquired in the data collecting step. The second pre-stored formula is a formula for calculating a ratio of predicted harvested eggs (predicted NROs) of the subject to an initial dose of the exogenous FSH drug administered to the subject using the age data of the subject obtained in the data collecting step, the basal anti-mullerian hormone (AMH) level data of the subject, the basal Follicle Stimulating Hormone (FSH) level data of the subject, and the basal sinus follicle count (AFC) data of the subject.
In the above method, the first formula is:
predicting NROs ═ EXP (a + b age + c basal FSH + d LN [ basal AMH ] + f LN [ basal AFC ]);
further, in said formula one,
a is any value of 1.5576128-2.6037078, preferably 2.0806603;
b is any value of-0.019097-0.0044064, preferably-0.007345;
c is selected from any value of-0.045234 to-0.004054, preferably-0.024644;
d is any value of 0.348168-0.4948875, preferably 0.4215277;
f is any value of 0.0415663-0.2566199, preferably 0.1490931.
In the above method, the second formula is:
predicted ovarian sensitivity in subjects, i.e., the predicted NROs/exogenous FSH drug initial dose calculated by equation one (EXP (g + h age + i basal FSH + j LN [ basal AMH ] + k basal AFC);
further, in the formula two,
g is selected from any value of-3.167587 to-2.751518, preferably-2.959552;
h is selected from any value of-0.025951 to-0.016355, preferably-0.021153;
i is selected from any value of-0.048143 to-0.025727, preferably-0.036935;
j is any value selected from 0.5174476-0.6075545, preferably 0.5625011;
k is any value of 0.0241595-0.0365579, preferably 0.0303587.
In the above method, the initial dose of the exogenous FSH drug administered to the subject may be calculated by dividing the predicted NROs calculated in equation one by the ratio calculated in equation two.
In the above method, the initial dose of the exogenous FSH drug administered to the subject may be calculated using equation three:
initial dose of exogenous FSH drug-Round (predicted NROs calculated by formula one/predicted ovarian sensitivity calculated by formula two, 0).
In one embodiment, the method of the present application is a method of predicting an adjusted dose of an exogenous FSH drug to be administered to a subject during a controlled ovarian stimulation cycle, wherein, in the data collection step, data is obtained of the subject's age, basal anti-mullerian hormone (AMH) level, basal sinus follicular count (AFC), and dynamic change in inhibin B level (Δ INHB); in the step of calculating the exogenous FSH medicament dose, the data acquired by the data acquisition module are calculated for the first time, so that the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation-promoting period is calculated; performing a second calculation on the data acquired by the data acquisition module, thereby calculating the ratio of the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation-promoting cycle to the adjusted dose of the exogenous FSH medicament, namely predicting the ovarian sensitivity; an adjusted dose of exogenous FSH drug to be administered to the subject is calculated based on the first calculated predicted egg counts (predicted NROs) and the second calculated ratio.
First, it should be appreciated that in the above method, data for age, basal anti-mullerian hormone (AMH) level, inhibin B level dynamic change (Δ INHB), basal sinus follicle count (AFC), actual number of eggs obtained, based on patients who have received standard GnRH antagonist regimens for ovulation induction treatment in an existing database, and a formula four for calculating predicted number of eggs obtained (predicted NROs) for a subject, fitted based on said pre-stored data for patients and a negative binomial distribution, are pre-stored. Using a pre-stored formula four, calculations can be performed for any subject to calculate predicted number of eggs (predicted NROs).
Furthermore, it is also understood that in the above method, data of the ratio of the predicted number of eggs obtained (predicted NROs) calculated by formula iv to the average daily dose of the exogenous FSH drug administered to the patient based on the age of the patient who had been subjected to ovulation induction treatment by the standard GnRH antagonist regimen, the level of basal anti-mullerian hormone (AMH), the dynamic change in inhibin B level (Δ INHB), the basal sinus follicle count (AFC), and the predicted number of eggs obtained (predicted NROs) calculated by formula iv, to the average daily dose of the exogenous FSH drug administered to the patient, and formula five for calculating the predicted ovarian sensitivity of the subject, i.e., the ratio of the predicted number of eggs obtained (predicted NROs) of the subject to the adjusted dose of the exogenous FSH drug administered to the subject, based on fitting of these data, are also previously stored. With the formula five pre-stored, the calculation can be performed for any subject.
In the present application, the average daily dose of the exogenous FSH drug administered to the patient is the ratio of the total dose of the exogenous FSH drug administered to the patient during the ovulation induction treatment with the standard GnRH antagonist regimen to the number of days the exogenous FSH drug is administered.
Specifically, the fourth pre-stored formula is fitted with pre-stored data based on the age, basal anti-mullerian hormone (AMH) level, inhibin B level dynamics (Δ INHB), basal sinus follicle count (AFC), and actual number of eggs obtained from patients who received standard GnRH antagonist regimens from existing databases. The fifth pre-stored formula is fitted with pre-stored data based on the ratio of the predicted number of eggs obtained (predicted NROs) calculated from the fourth formula to the average daily dose of exogenous FSH drug administered to the patient for ovulation induction treatment of patients receiving a standard GnRH antagonist regimen in an existing database, the basal anti-mullerian hormone (AMH) level, the dynamic change in inhibin B level (Δ INHB), the basal sinus follicle count (AFC).
In calculating, the fourth pre-stored formula is a formula for calculating predicted number of eggs obtained from the subject using the age data of the subject, the basal anti-mullerian hormone (AMH) level data of the subject, the inhibin B level dynamics (Δ INHB) data of the subject, and the basal sinus follicle count (AFC) data of the subject obtained by the data acquisition module. The fifth pre-stored equation is an equation that uses the data acquired by the data acquisition module for age data of the subject, basic anti-mullerian hormone (AMH) level data of the subject, inhibin B level dynamics (Δ INHB) data of the subject, and basic sinus follicle count (AFC) data of the subject to calculate a ratio of predicted harvested eggs (predicted NROs) of the subject to an adjusted dose of exogenous FSH medication administered to the subject.
In the above method, the formula four is: predicting NROs ═ EXP (w + m age + n LN [ basal AMH ] + o LN [ Δ INHB ] + p LN [ basal AFC ]);
further, in the formula four,
w is any value of-0.447201-0.9161863, preferably 0.2344927;
m is any value of-0.017165-0.0039328, preferably-0.006616;
n is any value of 0.1318094-0.3113979, preferably 0.2216036;
o is any value of 0.1901643-0.3850919, preferably 0.2876281;
p is any value of 0.0541966-0.2338079, preferably 0.1440023.
In the above method, the formula five is:
predicted ovarian sensitivity in subjects, i.e., the predicted NROs/exogenous FSH drug adjusted dose calculated by equation four, EXP (q + r age + s LN [ basal AMH ] + t basal AFC + u LN [ Δ INHB ]);
further, in the formula five, q is selected from any value of-5.63461 to-5.108612, preferably-5.371611;
r is selected from any value of-0.0264 to-0.015183, preferably-0.020792;
s is any value of 0.2696292-0.3684551, preferably 0.3190421;
t is any value of 0.0273504-0.0399372, preferably 0.0336438;
u is any value of 0.3327566-0.3940448, preferably 0.3634007.
In the above method, the adjusted dosage of exogenous FSH drug to be administered to the subject may be calculated by dividing the predicted NROs calculated in equation four by the ratio calculated in equation five.
In the above method, the adjusted dose of the exogenous FSH drug to be administered to the subject may be calculated using the formula six:
exogenous FSH drug adjusted dose-Round (predicted NROs calculated by equation four/predicted ovarian sensitivity calculated by equation five, 0).
The initial and adjusted doses of exogenous FSH predicted by the system or method of the present application are highly individualized and cannot be achieved with such accuracy with any current exogenous FSH product. Thus, ART physicians should select dosages that approximate our recommended dosages accordingly. For example, if the predicted starting dose is 70IU, 75IU may be selected instead.
Examples
1 Subjects for constructing models
Data obtained by 669 patients receiving treatment in the third hospital of Beijing university between 4 and 9 in 2020 is collected, and data obtained by 60 incomplete patients recorded by AFC, infertility reason or dosage and the like are further excluded, and model construction is carried out preliminarily. For a patient for preliminary model construction, the patient's basic and clinical characteristics are collected, including surname, case number, serial number, age, BMI index, duration of infertility, previous in vitro fertilization/intracytoplasmic sperm injectionNumber of sub-microinjection-embryo transfer (IVF/ICSI-ET) attempts, serum basal E 2 Levels, FSH and LH levels, serum AMH levels, left and right ovarian AFCs, first, second, third, fourth and fifth causes of infertility, conventional or mild ovarian stimulation cycles, ovarian stimulation type/COS regimen, initial and total doses of rFSH, duration of rFSH treatment (days), rFSH name, endometrial thickness on the day of human chorionic gonadotropin (hCG) trigger, date of oocyte retrieval and NROs.
2 COS treatment
The standard GnRH antagonist ovarian stimulation protocol was performed as follows: human rFSH (e.g., Gonal-F alfa [ Merck Serono, Germany)]，Puregon beta[MSD，USA]，Urofollitropin[Livzon Pharmaceutical Group Inc.，China]Or Menotropphins [ Livzon pharmaceutical group Inc., China]) Dosing began on day 2 of the menstrual cycle. The initial dose of human rFSH is selected based on age, AMH levels, basal FSH levels, AFC levels, BMI, and previous ovarian stimulation results. On day 6 of the menstrual cycle, the size and number of growing follicles observed by ultrasound and serum E during ovarian stimulation were monitored 2 The levels were further adjusted for rFSH dose. GnRH antagonist treatment was started when the diameter of the growing follicles reached 10-12 mm.
hCG (Chonogonodotropina alfa, Merck Serono) was injected at a dose of 5000-10000 IU to trigger final oocyte maturation when at least two dominant follicles were observed to be over 18mm in diameter by ultrasound. For the high risk population with ovarian hyperstimulation syndrome, the triggering was performed with a GnRH antagonist alone or in combination with 2000IU of hCG. Oocyte retrieval was performed 36-38 hours after hCG administration. Transferring one or two embryos or performing embryo cryopreservation. The patient or subject is then provided luteal phase progesterone support (progesterone vaginal gel, Merck Serono).
3 measurement of index for model construction
AFC was calculated by measuring follicles of 2-10mm diameter in both ovaries on day 2 of the menstrual cycle by transvaginal ultrasound scanning. Venous blood samples were drawn from the subjects using the hemagglutination on day two of menstruation. Wherein the content of the first and second substances,the next day of testing included AMH, inhibin B concentration, FSH, LH, E 2 Testosterone (T), progesterone (P), androstenedione (a 4). The test at the sixth day includes AMH, inhibin B concentration, LH, E 2 Testosterone (T), progesterone (P), androstenedione (a 4). Wherein, serum FSH, LH, E 2 Measurements of P, T and A4 were all performed using the Siemens Immunite 2000 immunoassay system (Siemens healthcare Diagnostics, Shanghai, China).
FSH、LH、E 2 And progesterone measurements were both performed using the Siemens Immulite 2000 immunoassay system (Siemens healthcare Diagnostics, Shanghai, PR China). FSH, LH and E 2 The tertiary quality Control of (2) was provided by Bio-RAD laboratories (lymphochek Immunoassay Plus Control, Trilevel, Cat. No. 370, batch No. 40390). Serum AMH concentration and inhibin B concentration were measured using an ultrasensitive ELISA (Ansh Laboratories, Webster, TX, USA) kit, using the quality control provided by the kit. For AMH, inhibin B, FSH and LH, the three-level or two-level control of the measured coefficient of variation was less than 5%, respectively. For E 2 T and a4, the coefficient of variation being determined to be less than 10% for each of the three or two stages of control. The measurement results are shown in table 1.
TABLE 1
Figure BDA0003765900320000301
Figure BDA0003765900320000311
Note: numerical values are expressed as median; delta levels, day 6 minus 2 of different ovarian reserve markers
Dynamic level of day; BMI, body mass index; t, testosterone; p, progesterone; a4, androstenedione (a 4);
NA, not applicable.
Meanwhile, the average daily dose of the used exogenous FSH (the ratio of the total dose of the used exogenous FSH medicament to the days of the used exogenous FSH medicament), the main reason of infertility, the brand of the used exogenous FSH medicament and different ovarian stimulation results are also analyzed, and the following tables 2 to 4 show the results.
TABLE 2
Figure BDA0003765900320000312
TABLE 3
Figure BDA0003765900320000313
Note: urofollitropin, high purity Urofollitropin for injection; HMG, high purity for injection
Menopausal Gonadotropins (HMGs) in urologic humans; BMI, body mass index; t, testosterone; a4,
Androstenedione.
TABLE 4
Figure BDA0003765900320000314
Figure BDA0003765900320000321
Note: PN, prokaryotic.
Construction of 4 predictive initial dose system model
In the application, when the initial dose of the exogenous FSH medicament administered to a subject in a controlled ovarian stimulation cycle is predicted, two models are sequentially constructed, firstly, a first model for predicting NROs obtained by the subject in an ovulation-promoting cycle is constructed, then, a second model is constructed based on the NROs predicted by the first model, and the second model is a model for obtaining the ratio of the predicted number of obtained eggs (predicted NROs) of the subject in the ovulation-promoting cycle to the initial dose of the exogenous FSH medicament administered to the subject in the ovulation-promoting cycle, namely, a model for predicting the ovarian sensitivity of the subject. The initial variables for model one and model two inclusion were consistent, and were age, BMI, cause of infertility, basal FSH, AFC, day two and day six AMH, inhibin B, LH, E 2 P, testosterone and androstenedione levels.
4.1 model one
In model one, the distribution of the number of oocytes harvested was first determined for the 609 patient data described above. Since the number of oocytes obtained is count data, which can be considered as poisson distribution or negative binomial distribution, the number of eggs obtained for 609 patients in this embodiment is more consistent with the negative binomial distribution. In this embodiment, a negative binomial regression is selected to construct a statistical model i, a forward pruning method and a 30% holdback verification are adopted for selection of prediction indexes, a software JMP Pro v.16 is used to construct a prediction model, and a data set consisting of the 609 patients is randomly divided into two parts, one part is used as a training set (426 data, 70%), and the other part is used as a verification set (183 data, 30%).
First, modeling is performed in a training set, and model effects are verified in a verification set. The prediction model is selected mainly according to the negative log-likelihood value in the verification set, and the lower the negative log-likelihood value in the verification set is, the better the prompt model is.
When 4 variables are included, the scaled-Log L (β) no longer decreases, so the 4 variables ln [ basal AMH ], ln [ basal AFC ], age, and basal FSH are ultimately included in the model according to their importance. The results of the parameter estimation of each variable in this prediction model are shown in table 5, and the 95% confidence intervals for each parameter are further shown in table 5.
TABLE 5 estimation of parameters for prediction model one
Figure BDA0003765900320000322
Figure BDA0003765900320000331
Based on the above method, the following formula one is confirmed in the present embodiment:
NROs ═ EXP (a + b age + c basal FSH + d LN [ basal AMH ] + f LN [ basal AFC ]);
wherein NROs represent mature oocyte number; age represents the age of the subject; basal FSH represents the basal follicle stimulating hormone level prior to ovulation induction treatment of the subject; basal AMH represents the basal anti-mullerian hormone level of the subject prior to ovulation-promoting treatment; basal AFC indicates the number of all visible follicles with a diameter of 2-10mm in both ovaries of the subject on day 2 of menstruation.
In a specific embodiment, AMH refers to the concentration of anti-mullerian hormone in venous blood of a subject at any time point during the menstrual period prior to ovulation induction treatment. FSH refers to the follicle stimulating hormone concentration in the venous blood of menses day 2 prior to ovulation induction treatment in a female subject. AFC refers to the number of all visible follicles with a diameter of 2-10mm in both ovaries on day 2 of menstruation of a female subject before ovulation induction treatment.
In the formula I, a is any value selected from 1.5576128-2.6037078, and a is preferably 2.0806603;
b is any value of-0.019097-0.0044064, and b is preferably-0.007345;
c is any value selected from-0.045234 to-0.004054, and c is preferably-0.024644;
d is any value of 0.348168-0.4948875, preferably 0.4215277;
f is any value of 0.0415663-0.2566199, and f is preferably 0.1490931.
The predicted effect of model one constructed for the training set and the validation set using the above method is shown in table 6. Therefore, the first constructed model obtains a good prediction effect in both a training set and a verification set, and the predicted data has high coincidence degree with the actual detection data.
TABLE 6 Performance of model one in training and validation sets
Figure BDA0003765900320000332
Figure BDA0003765900320000341
4.2 model two
In model two, the outcome variable was ovarian sensitivity, i.e. the ratio of the number of eggs taken (NORs) predicted by model one to the initial dose of exogenous FSH, for the data of the above 609 patients. According to model one, the predicted NROs were calculated using basal AMH, basal AFC, basal FSH and age 4 basal predictors with main effects (contribution) of 90.2%, 3.6%, 1.2%, 0.3%, respectively.
4.2.1 normalization test of result variables
The resulting variables, i.e., the ratio of NROs to exogenous FSH predicted using the basal predictor, were first examined for normality. The results show a skewed distribution (Shapiro-Wilk test, W-0.8691) (fig. 1A), which approximates a log-normal distribution and therefore allows for a logarithmic transformation. After log transformation, it is closer to normal distribution (Shapiro-Wilk test, W-0.9907) (fig. 1B), so subsequent analysis all have log transformation of the resulting variables as dependent variables.
4.2.2 Linear relationship exploration of Primary variables
Linear relationships between each independent variable and dependent variable are separately explored. Most variables, except AMH, are linear. AMH is non-linear with the results (fig. 1C). The AMH is subjected to logarithmic transformation, and the goodness of fit after the logarithmic transformation is obviously superior to that before the transformation, R before the transformation 2 0.6574, post-conversion R 2 Is 0.8643. Thus, in subsequent analysis, AMH is analyzed in logarithmic form, and other independent variables are not transformed.
4.2.3 screening of predictor variables Using lasso regression
All predictors were screened using lasso regression. First, the data were randomly divided into a training set and a validation set at a ratio of 0.7: 0.3. The best subset method is used for variable selection. The variable screening process is shown in fig. 2A and 2B. When 4 variables were included, the scale-LogL (β) values in the validation set no longer decreased. R of the model 2 0.911 and 0.923 in the training and validation sets, respectively. The RMSE for the training and validation sets were 0.237 and 0.224, respectively. The four variables of basic AMH, AFC, basic FSH and age for logarithmic transformation are finally included in the model for predicting the initial dose of exogenous FSH, i.e. the modelAnd in type two. The contributions of the four predictors were evaluated by the main and total effects, respectively, and the results are shown in fig. 2C, where the AMH contribution is maximal. The results of the parameter estimation of each variable in this prediction model are shown in table 7, and the 95% confidence intervals of each parameter are further shown in table 7.
TABLE 7 results of parameter estimation of prediction models
Figure BDA0003765900320000351
Based on the above method, the following formula two is confirmed in the present embodiment.
Formula one initial dose of NROs/exogenous follicle stimulating hormone (EXP (g + h age + i basic FSH + j LN [ basic AMH ] + k basic AFC)
Wherein NROs represent mature oocyte number; age represents the age of the subject; AFC represents the number of all visible follicles with a diameter of 2-10mm in two ovaries of the subject on day 2 of menstruation; basal AMH represents the basal anti-mullerian hormone level of the subject prior to ovulation-promoting treatment; basal FSH represents the basal follicle stimulating hormone level prior to ovulation induction treatment of a subject.
In a specific embodiment, AMH refers to the concentration of anti-mullerian hormone in venous blood of a subject at any time point during the menstrual period prior to ovulation induction treatment. AFC refers to the number of all visible follicles with a diameter of 2-10mm in both ovaries on day 2 of menstruation of a female subject before ovulation induction treatment. FSH refers to the follicle stimulating hormone concentration in the venous blood of menses day 2 prior to ovulation induction treatment in a female subject.
In the formula (II), g is selected from any value of-3.167587 to-2.751518, preferably-2.959552;
h is selected from any value of-0.025951 to-0.016355, preferably-0.021153;
i is selected from any value of-0.048143 to-0.025727, preferably-0.036935;
j is any value selected from 0.5174476-0.6075545, preferably 0.5625011;
k is any value of 0.0241595-0.0365579, preferably 0.0303587.
Finally, the initial dose of exogenous FSH drug administered to the subject is calculated using equation three:
initial dose of exogenous FSH drug-Round (predicted NROs calculated by formula one/predicted ovarian sensitivity calculated by formula two, 0).
The effect of predicting the initial dose of exogenous FSH for model two constructed by the training set and the validation set using the above method is shown in table 8 and a scatter plot showing the relationship between the predicted outcome variables and the actual outcome variables. If the prediction is completely consistent with the actual result, the scattered points are completely distributed on the diagonal; as shown in fig. 2D and 2E, the points are evenly distributed on both sides of the diagonal, indicating good prediction performance. The residual map is also used to estimate the effect, and the ideal fit should be evenly distributed on the diagonal; as shown in fig. 2F and 2G, the points are also uniformly distributed on both sides of the diagonal line in the residual error map, and are normally distributed, and the prediction deviation is small. All these results indicate that model two has good predictive performance.
TABLE 8 Performance of model two in training and validation sets
Figure BDA0003765900320000361
5 construction of predictive adjusted dosing System model
When the adjusting dosage of the exogenous FSH drug given to the subject in the controlled ovarian stimulation period is predicted, two models are sequentially constructed, firstly, a third model for predicting NROs obtained by the subject in the ovulation-promoting period is constructed, and then, a fourth model is constructed based on the NROs predicted by the third model, wherein the fourth model is a model for obtaining the ratio of the predicted number of obtained eggs (predicted NROs) of the subject in the ovulation-promoting period to the adjusting dosage of the exogenous FSH drug given to the subject in the ovulation-promoting period, namely a model for predicting the ovarian sensitivity of the subject. Initial variables for model three and model four inclusion were consistent, and were age, BMI, cause of infertility, basal FSH, AFC, AMH, inhibin B, LH, E on day two and day six 2 P, testosterone and androstenedione levels.
5.1 model III
In model three, the distribution of the number of oocytes harvested was first determined for the 609 patient data described above. Since the number of oocytes obtained is count data, which can be considered as poisson distribution or negative binomial distribution, the number of eggs obtained for 609 patients in this embodiment is more consistent with the negative binomial distribution. In this embodiment, a negative binomial regression is selected to construct a third statistical model, a forward pruning method and a 30% holdback verification are adopted for selection of prediction indexes, a software JMP Pro v.16 is used to construct a prediction model, and a data set consisting of the 609 patients is randomly divided into two parts, one part is used as a training set (426 data, 70%), and the other part is used as a verification set (183 data, 30%).
First, modeling is performed in a training set, and model effects are verified in a verification set. The prediction model is selected mainly according to the negative log-likelihood value in the verification set, and the lower the negative log-likelihood value in the verification set is, the better the prompt model is.
When 4 variables are included, the scaled-Log L (β) no longer decreases, so the 4 variables ln [ Δ INHB ], ln [ base AMH ], AFC, and age are ultimately included in the model according to their importance. The results of the parameter estimation of each variable in this prediction model are shown in table 9, and the 95% confidence intervals of each parameter are further shown in table 9.
TABLE 9 results of parameter estimation for prediction model III
Figure BDA0003765900320000371
Based on the above method, the following formula four is confirmed in the present embodiment:
predicting NROs ═ EXP (w + m age + n LN [ basal AMH ] + o LN [ Δ INHB ] + p LN [ basal AFC ]);
wherein NROs represent mature oocyte number; age represents the age of the subject; Δ INHB represents the dynamic change in inhibin B levels early in the course of ovulation-promoting treatment in a subject; basal AMH represents the basal anti-mullerian hormone level of the subject prior to ovulation-promoting treatment; basal AFC indicates the number of all visible follicles with a diameter of 2-10mm in both ovaries of the subject on day 2 of menstruation.
In a specific embodiment, AMH refers to the concentration of anti-mullerian hormone in venous blood of a subject at any time point during the menstrual period prior to ovulation induction treatment. Δ INHB refers to the difference between the serum inhibin B concentration at day 6 of menses and the intravenous blood concentration at day 2 of menses in female subjects undergoing treatment with a GnRH antagonist regimen to promote ovulation. AFC refers to the number of all visible follicles with a diameter of 2-10mm in two ovaries of a female subject on day 2 of menstruation before ovulation induction treatment.
In the formula IV, w is any value selected from-0.447201-0.9161863, preferably 0.2344927;
m is any value of-0.017165-0.0039328, preferably-0.006616;
n is any value of 0.1318094-0.3113979, preferably 0.2216036;
o is any value of 0.1901643-0.3850919, preferably 0.2876281;
p is any value of 0.0541966-0.2338079, preferably 0.1440023.
The prediction effect of the model III constructed by the method aiming at the training set and the verification set is shown in the table 10, so that the constructed model III obtains good prediction effect in the training set and the verification set, and the predicted data has high coincidence degree with the actual detection data.
TABLE 10 Performance of model III in training and validation sets
Figure BDA0003765900320000381
5.2 model four
In model four, for the data of the 609 patients described above, the outcome variable was ovarian sensitivity, i.e., the ratio of the number of eggs removed (NORs) predicted by model one to the initial dose of exogenous FSH. According to model three, the predicted NROs were calculated using the inhibin B level dynamics (day 6 minus day 2), basal AMH, basal AFC and age 4 basal predictors with main effects (contribution) of 48.9%, 30.0%, 12.7% and 2.0%, respectively, and total effects (contribution) of 50.8%, 31.8%, 14.5% and 3.2%, respectively.
5.2.1 normalization test of result variables
The resulting variables, i.e., the ratio of NROs to exogenous FSH predicted using the basal predictor, were first examined for normality. The results show a skewed distribution (Shapiro-Wilk test, W-0.8522) that approximates a log-normal distribution, and therefore a logarithmic transformation is considered. After log transformation, it is closer to normal distribution (Shapiro-Wilk test, W-0.9916), so subsequent analysis all have the log transformation of the resulting variable as the dependent variable.
5.2.2 Linear relationship exploration of Primary variables
Linear relationships between each independent variable and dependent variable are separately explored. Most variables are in linear relation, but AMH, inhibin B level and inhibin B level dynamic change are in obvious nonlinear relation with results, the 3 variables are subjected to logarithmic transformation, and the goodness of fit after logarithmic transformation is obviously superior to that before transformation. For AMH, R before transformation 2 Is 0.5829, R after transformation 2 0.7904; for inhibin B levels, pre-conversion R 2 0.2255, post-conversion R 2 0.2608; for dynamic changes in inhibin B levels, pre-conversion R 2 0.5613, post-conversion R 2 Is 0.7247. Therefore, in the subsequent analysis, AMH, inhibin B level dynamics were analyzed in logarithmic form, and other independent variables were not transformed.
5.2.3 screening of predictor variables Using lasso regression
All predictors were screened using lasso regression. First, the data were randomly divided into a training set and a validation set at a ratio of 0.7: 0.3. The best subset method is used for variable selection. The variable screening process is shown in fig. 3A and 3B. When 4 variables are included, the scale-LogL (β) values in the validation set are not substantially reduced. R of the model 2 0.922 and 0.909 in the training set and validation set, respectively. RMSE of training set and validation set are respectively0.236 and 0.231. The four variables of base AMH for logarithmic conversion, Δ INHB for logarithmic conversion, AFC and age were finally included in the model predicting the adjusted dose of exogenous FSH, i.e. model four. The contributions of the four predictors were evaluated by the main and total effects, respectively, and the results are shown in fig. 3C, where Δ INHB contribution is maximal. The results of the parameter estimation of each variable in this prediction model are shown in table 11, and the 95% confidence intervals of each parameter are further shown in table 11.
TABLE 11 results of parameter estimation of prediction models
Figure BDA0003765900320000391
Based on the above method, the following formula five is confirmed in the present embodiment.
The adjusted dose of NROs/exogenous follicle-stimulating hormone calculated by equation five is EXP (q + r age + s LN [ basal AMH ] + t basal AFC + u LN [ Δ INHB ]);
wherein NROs represent mature oocyte number; age represents the age of the subject; AFC represents the number of all visible follicles with a diameter of 2-10mm in two ovaries of the subject on day 2 of menstruation; basal AMH represents basal anti-mullerian hormone levels prior to ovulation induction treatment in a subject; Δ INHB represents the dynamic change in inhibin B levels early in the course of ovulation-promoting treatment in a subject.
In a specific embodiment, AMH refers to the concentration of anti-mullerian hormone in venous blood of a subject at any time point during the menstrual period prior to ovulation induction treatment. AFC refers to the number of all visible follicles with a diameter of 2-10mm in both ovaries on day 2 of menstruation of a female subject before ovulation induction treatment. Δ INHB refers to the difference between the serum inhibin B concentration at day 6 of menses and the intravenous blood concentration at day 2 of menses in female subjects undergoing treatment with a GnRH antagonist regimen to promote ovulation.
In the formula five, q is selected from any value of-5.63461 to-5.108612, preferably-5.371611;
r is selected from any value of-0.0264 to-0.015183, preferably-0.020792;
s is any value of 0.2696292-0.3684551, preferably 0.3190421;
t is any value of 0.0273504-0.0399372, preferably 0.0336438;
u is any value of 0.3327566-0.3940448, preferably 0.3634007.
The effect of predicting the adjustment dose of exogenous FSH for model four constructed by the training set and the validation set using the above method is shown in table 12 and a scatter plot showing the relationship between the predicted outcome variables and the actual outcome variables. If the prediction is completely consistent with the actual result, the scattered points are completely distributed on the diagonal; as shown in fig. 3D and 3E, the scatter dots are evenly distributed on both sides of the diagonal, indicating good prediction performance. The residual map is also used to estimate the effect, and the ideal fit should be evenly distributed on the diagonal; as shown in fig. 3F and 3G, the scatter points are also uniformly distributed on both sides of the diagonal line in the residual error map, and are normally distributed, so that the prediction deviation is small. All these results indicate that model four has good predictive performance.
TABLE 12 Performance of model four in training and validation sets
Figure BDA0003765900320000401
Although the embodiments of the present application have been described above with reference to the accompanying drawings, the present application is not limited to the above-described embodiments and application fields, and the above-described embodiments are illustrative, instructive, and not restrictive. Those skilled in the art, having the benefit of this disclosure, may effect numerous modifications to the disclosed embodiments without departing from the scope of the claimed invention, as defined by the appended claims.

Claims (10)

1. A system for predicting a dose of an exogenous Follicle Stimulating Hormone (FSH) drug administered to a subject in a controlled ovarian stimulation cycle, comprising:
a data acquisition module for acquiring data of age, basal anti-mullerian hormone (AMH) level, basal Follicle Stimulating Hormone (FSH) level or inhibin B level dynamic change (Δ INHB), basal sinus follicle count (AFC) of a subject; and
an exogenous Follicle Stimulating Hormone (FSH) drug dose calculation module to: calculating the data acquired by the data acquisition module for the first time so as to calculate the predicted number of eggs (predicted NROs) of the subject in the ovulation promoting period; performing a second calculation on the data acquired by the data acquisition module, thereby calculating the ratio of the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation induction cycle to the dosage of the exogenous FSH medicament, namely predicting the ovarian sensitivity; the dose of exogenous FSH drug to be administered to the subject is calculated based on the first calculated predicted egg counts (predicted NROs) and the second calculated ratio.
2. The system of claim 1, wherein,
the data acquisition module is for acquiring data of age, basal anti-mullerian hormone (AMH) level, basal Follicle Stimulating Hormone (FSH) level, basal Antral Follicle Count (AFC) of the subject;
the exogenous Follicle Stimulating Hormone (FSH) drug dose calculation module is configured to: calculating the data acquired by the data acquisition module for the first time so as to calculate the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation induction period; performing a second calculation on the data acquired by the data acquisition module, thereby calculating the ratio of the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation induction cycle to the initial dose of the exogenous FSH medicament, namely predicting the ovarian sensitivity; an initial dose of exogenous FSH drug to be administered to the subject is calculated based on the first calculated predicted egg counts (predicted NROs) and the second calculated ratio.
3. The system of claim 2, wherein,
the exogenous FSH medicament dose calculation module is used for storing a formula I for calculating predicted egg-harvesting number (predicted NROs) of a subject, which is obtained by fitting data of age, basic anti-mullerian hormone (AMH) level, basic Follicle Stimulating Hormone (FSH) level, basic Antral Follicle Count (AFC) and actual egg-harvesting number of a patient subjected to ovulation promotion treatment by a standard GnRH antagonist scheme in an existing database;
preferably, the first formula is:
predicting NROs ═ EXP (a + b age + c basal FSH + d LN [ basal AMH ] + f LN [ basal AFC ]);
wherein a is any value selected from 1.5576128-2.6037078, preferably 2.0806603;
b is any value of-0.019097-0.0044064, preferably-0.007345;
c is selected from any value of-0.045234 to-0.004054, preferably-0.024644;
d is any value of 0.348168-0.4948875, preferably 0.4215277;
f is any value of 0.0415663-0.2566199, preferably 0.1490931.
4. The system of claim 3, wherein,
in the exogenous FSH medicament dose calculation module, a second formula for calculating the predicted ovarian sensitivity of the subject, namely the ratio of the predicted number of eggs (predicted NROs) to the initial dose of the exogenous FSH medicament, which is obtained by fitting data of the ratio of the predicted number of eggs (predicted NROs) calculated by the first formula to the average daily dose of the exogenous FSH medicament used by the patient based on the age, the level of basic anti-Mullerian hormone (AMH), the level of basic Follicle Stimulating Hormone (FSH), the basic Antral Follicle Count (AFC) of a patient who is subjected to ovulation promotion treatment by a standard GnRH antagonist scheme in an existing database, is stored in advance;
wherein the average daily dose of exogenous FSH drug administered to said patient is the ratio of the total dose of exogenous FSH drug administered to said patient during the past treatment period of ovulation induction using the standard GnRH antagonist regimen to the number of days that exogenous FSH drug is administered.
5. The system of claim 4, wherein the formula two is:
predicted ovarian sensitivity of the subject, i.e., predicted NROs/exogenous FSH drug initial dose calculated according to formula one EXP (g + h age + i basal FSH + j LN [ basal AMH ] + k basal AFC), wherein g is selected from any of-3.167587 to-2.751518, preferably-2.959552;
h is selected from any value of-0.025951 to-0.016355, preferably-0.021153;
i is selected from any value of-0.048143 to-0.025727, preferably-0.036935;
j is any value selected from 0.5174476-0.6075545, preferably 0.5625011;
k is any value of 0.0241595-0.0365579, preferably 0.0303587.
6. The system of claim 1, wherein,
the data acquisition module is used for acquiring data of age, basal anti-mullerian hormone (AMH) level, basal Antral Follicle Count (AFC) and inhibin B level dynamic change (delta INHB) of a subject;
the exogenous Follicle Stimulating Hormone (FSH) drug dose calculation module is to: calculating the data acquired by the data acquisition module for the first time so as to calculate the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation induction period; performing a second calculation on the data acquired by the data acquisition module, thereby calculating the ratio of the predicted number of eggs (predicted NROs) acquired by the subject in the ovulation-promoting cycle to the adjusted dose of the exogenous FSH medicament, namely predicting the ovarian sensitivity; an adjusted dose of exogenous FSH drug to be administered to the subject is calculated based on the first calculated predicted egg counts (predicted NROs) and the second calculated ratio.
7. The system of claim 6, wherein,
in the exogenous FSH drug dose calculation module, namely according to the dynamic change index and the basic index of the ovulation-promoting treatment early stage, the method comprises a fourth formula which is stored in advance and is used for calculating the predicted number of eggs obtained (predicted NROs) of the subject, wherein the fourth formula is formed by fitting data which are obtained based on the age, the basic anti-Mullerian hormone (AMH) level, the basic sinus follicle count (AFC), the inhibin B level dynamic change (delta INHB) and the actual number of eggs obtained of a patient who is subjected to ovulation-promoting treatment by a standard GnRH antagonist scheme in an existing database.
8. The system of claim 7, wherein the formula four is:
predicting NROs ═ EXP (w + m × age + n × LN [ basal AMH ] + o × LN [ Δ INHB ] + p × LN [ basal AFC ]);
wherein w is any value selected from-0.447201-0.9161863, preferably 0.2344927;
m is any value of-0.017165-0.0039328, preferably-0.006616;
n is any value of 0.1318094-0.3113979, preferably 0.2216036;
o is any value of 0.1901643-0.3850919, preferably 0.2876281;
p is any value of 0.0541966-0.2338079, preferably 0.1440023.
9. The system of claim 8, wherein,
in the exogenous FSH medicament dose calculation module, a fifth formula for calculating the predicted ovarian sensitivity of the subject, namely the ratio of the predicted number of eggs obtained (predicted NROs) to the adjusted dose of the exogenous FSH medicament, is stored in advance, wherein the fifth formula is formed by fitting data of the ratio of the predicted number of eggs obtained (predicted NROs) calculated by the fourth formula to the average daily dose of the exogenous FSH medicament used by the patient, the data of the age, the level of basic anti-Mullerian hormone (AMH), the basic sinus follicle count (AFC), the dynamic change of inhibin B level (delta INHB) of the patient subjected to ovulation promotion treatment by the standard GnRH antagonist scheme in the existing database;
wherein the average daily dose of the exogenous FSH drug administered to the patient is the ratio of the total dose of the exogenous FSH drug administered to the patient during the past ovulation induction treatment with the standard GnRH antagonist regimen to the number of days the exogenous FSH drug was administered.
10. The system of claim 9, wherein the formula five is:
predicted ovarian sensitivity in subjects, i.e., the predicted NROs/exogenous FSH drug adjusted dose calculated by equation four (q + r age + s LN [ basal AMH ] + t basal AFC + u LN [ Δ INHB ])
Wherein q is any value selected from-5.63461 to-5.108612, preferably-5.371611;
r is selected from any value of-0.0264 to-0.015183, preferably-0.020792;
s is any value of 0.2696292-0.3684551, preferably 0.3190421;
t is any value of 0.0273504-0.0399372, preferably 0.0336438;
u is any value of 0.3327566-0.3940448, preferably 0.3634007.
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